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Bhattarai P, Yilmaz E, Cakir EÖ, Korkmaz HY, Lee AJ, Ma Y, Celikkaya H, Cosacak MI, Haage V, Wang X, Nelson N, Lin W, Zhang Y, Nuriel T, Jülich D, Iş Ö, Holley SA, de Jager P, Fisher E, Tubbesing K, Teich AF, Bertucci T, Temple S, Ertekin-Taner N, Vardarajan BN, Mayeux R, Kizil C. APOE- ε4-induced Fibronectin at the blood-brain barrier is a conserved pathological mediator of disrupted astrocyte-endothelia interaction in Alzheimer's disease. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.01.24.634732. [PMID: 39975303 PMCID: PMC11838230 DOI: 10.1101/2025.01.24.634732] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/21/2025]
Abstract
Blood-brain barrier (BBB) dysfunction is a key feature of Alzheimer's disease (AD), particularly in individuals carrying the APOE-ε4 allele. This dysfunction worsens neuroinflammation and hinders the removal of toxic proteins, such as amyloid-beta (Aβ42), from the brain. In post-mortem brain tissues and in animal models, we previously reported that fibronectin accumulates at the BBB predominantly in APOE-ε4 carriers. Furthermore, we found a loss-of-function variant in the fibronectin 1 ( FN1 ) gene significantly reduces aggregated fibronectin levels and decreases AD risk among APOE-ε4 carriers. Yet, the molecular mechanisms downstream of fibronectin at the BBB remain unclear. The extracellular matrix (ECM) plays a crucial role in maintaining BBB homeostasis and orchestrating the interactions between BBB cell types, including endothelia and astrocytes. Understanding the mechanisms affecting the ECM and BBB cell types will be critical for developing effective therapies against AD, especially among APOE-ε4 carriers. Here, we demonstrate that APOE-ε4 , Aβ42, and inflammation drive the induction of FN1 expression in several models including zebrafish, mice, iPSC-derived human 3D astrocyte and 3D cerebrovascular cell cultures, and in human brains. Fibronectin accumulation disrupts astroglial-endothelial interactions and the signalling cascade between vascular endothelial growth factor (VEGF), heparin-binding epidermal growth factor (HBEGF) and Insulin-like growth factor 1 (IGF1). This accumulation of fibronectin in APOE-ε4- associated AD potentiates BBB dysfunction, which strongly implicates reducing fibronectin deposition as a potential therapeutic target for AD. Graphical abstract Accessibility text This image illustrates the effects of different APOE isoforms (ApoE-ε3 and ApoE-ε4) on blood-brain barrier (BBB) integrity, focusing on the molecular interactions between astrocytes and endothelial cells. This figure emphasizes the detrimental effects of ApoE-ε4 on BBB integrity via fibronectin accumulation and altered signaling pathways. The top section provides a schematic overview of the blood-brain barrier, highlighting astrocytes, endothelial cells, and their interface. The left panel represents the ApoE-ε3 condition: Normal fibronectin (FN1) levels support healthy interactions between astrocytes and endothelial cells. Growth factors, including VEGFA, HBEGF, and IGF1, maintain BBB integrity through their respective receptors (VEGFR and EGFR). Green arrows indicate activation of these signaling pathways. The right panel depicts the ApoE-ε4 condition: Elevated fibronectin (FN1) disrupts astrocyte-endothelium interactions. FN1 binds integrins and activates focal adhesion kinase (FAK), inhibiting VEGFA, which is required for endothelial HBEGF that in turn activates IGF1 signaling. Red symbols indicate inhibition of HBEGF, VEGFA, and IGF1 pathways, leading to BBB dysfunction. Highlights APOE-ε4 drives fibronectin deposition in Alzheimer's, disrupting astrocyte-endothelia interactions. APOE-ε4 and fibronectin co-localize, forming aggregates at blood-brain barrier (BBB). Fibronectin alters the signaling between VEGF, IGF1, and HBEGF impairing BBB function. Reducing fibronectin restores BBB integrity and offsets APOE-ε4 pathology.
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Srivastava PP, Bhasin S, Shankaran SS, Roger C, Ramachandran R, Minocha S. A reproducible method to study traumatic injury-induced zebrafish brain regeneration. Biol Methods Protoc 2024; 9:bpae073. [PMID: 39464854 PMCID: PMC11502497 DOI: 10.1093/biomethods/bpae073] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2024] [Revised: 09/13/2024] [Indexed: 10/29/2024] Open
Abstract
Traumatic brain injury (TBI) can be caused by a sudden blow or jolt to the head, causing irreversible brain damage leading to cellular and functional loss. Mammals cannot repair such damage, which may increase the risk of progressive neurodegeneration. Unlike mammals, lower vertebrates such as zebrafish have the astounding capability to regenerate their brains. A model system would be of great value to study zebrafish brain regeneration. Here, we describe a physical method to induce traumatic injury in the zebrafish brain and outline a pipeline to utilize this model system to explore various aspects of brain regeneration. This will significantly advance the fields of regenerative biology and neuroscience. The method includes inducing TBI and validating this through histological assays, immunohistochemistry, and gene expression analysis. By using this model system, researchers will be able to gain valuable insights into the cellular and molecular mechanisms underlying brain regeneration. Understanding these mechanisms could lead to the identification of potential strategies to address neurodegenerative conditions in higher vertebrates.
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Affiliation(s)
- Priyanka P Srivastava
- Kusuma School of Biological Sciences, Indian Institute of Technology Delhi, Hauz Khas, New Delhi, 110016, India
| | - Sidharth Bhasin
- Kusuma School of Biological Sciences, Indian Institute of Technology Delhi, Hauz Khas, New Delhi, 110016, India
| | - Sunita S Shankaran
- Kusuma School of Biological Sciences, Indian Institute of Technology Delhi, Hauz Khas, New Delhi, 110016, India
- Regional Centre for Biotechnology, 3rd Milestone, Faridabad-Gurgaon Expressway, Faridabad, 121001, India
| | - Catherine Roger
- Phenotyping Facility, Centre of Integrative Biology, Genopode, University of Lausanne, Lausanne, 1015, Switzerland
| | | | - Shilpi Minocha
- Kusuma School of Biological Sciences, Indian Institute of Technology Delhi, Hauz Khas, New Delhi, 110016, India
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Chen J, Sanchez-Iranzo H, Diotel N, Rastegar S. Comparative insight into the regenerative mechanisms of the adult brain in zebrafish and mouse: highlighting the importance of the immune system and inflammation in successful regeneration. FEBS J 2024; 291:4193-4205. [PMID: 39108082 DOI: 10.1111/febs.17231] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2024] [Revised: 06/17/2024] [Accepted: 07/18/2024] [Indexed: 10/04/2024]
Abstract
Regeneration, the complex process of restoring damaged or absent cells, tissues, and organs, varies considerably between species. The zebrafish is a remarkable model organism for its impressive regenerative abilities, particularly in organs such as the heart, fin, retina, spinal cord, and brain. Unlike mammals, zebrafish can regenerate with limited or absent scarring, a phenomenon closely linked to the activation of stem cells and immune cells. This review examines the unique roles played by the immune response and inflammation in zebrafish and mouse during regeneration, highlighting the cellular and molecular mechanisms behind their divergent regenerative capacities. By focusing on zebrafish telencephalic regeneration and comparing it to that of the rodents, this review highlights the importance of a well-controlled, acute, and non-persistent immune response in zebrafish, which promotes an environment conducive to regeneration. The knowledge gained from understanding the mechanisms of zebrafish regeneration holds great promises for the treatment of human neurodegenerative diseases and brain damage (stroke and traumatic brain injuries), as well as for the advancement of regenerative medicine approaches.
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Affiliation(s)
- Jincan Chen
- Institute of Biological and Chemical Systems-Biological Information Processing (IBCS-BIP), Karlsruhe Institute of Technology (KIT), Germany
| | - Hector Sanchez-Iranzo
- Institute of Biological and Chemical Systems-Biological Information Processing (IBCS-BIP), Karlsruhe Institute of Technology (KIT), Germany
| | - Nicolas Diotel
- Université de La Réunion, INSERM, UMR 1188, Diabète Athérothrombose Thérapies Réunion Océan Indien (DéTROI), Saint-Pierre, La Réunion, France
| | - Sepand Rastegar
- Institute of Biological and Chemical Systems-Biological Information Processing (IBCS-BIP), Karlsruhe Institute of Technology (KIT), Germany
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4
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Latham AS, Rocha SM, McDermott CP, Reigan P, Slayden RA, Tjalkens RB. Neuroprotective efficacy of the glucocorticoid receptor modulator PT150 in the rotenone mouse model of Parkinson's disease. Neurotoxicology 2024; 103:320-334. [PMID: 38960072 PMCID: PMC11796432 DOI: 10.1016/j.neuro.2024.06.017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2024] [Revised: 06/17/2024] [Accepted: 06/28/2024] [Indexed: 07/05/2024]
Abstract
Parkinson's disease (PD) is the most common neurodegenerative movement disorder worldwide. Current treatments for PD largely center around dopamine replacement therapies and fail to prevent the progression of pathology, underscoring the need for neuroprotective interventions. Approaches that target neuroinflammation, which occurs prior to dopaminergic neuron (DAn) loss in the substantia nigra (SN), represent a promising therapeutic strategy. The glucocorticoid receptor (GR) has been implicated in the neuropathology of PD and modulates numerous neuroinflammatory signaling pathways in the brain. Therefore, we investigated the neuroprotective effects of the novel GR modulator, PT150, in the rotenone mouse model of PD, postulating that inhibition of glial inflammation would protect DAn and reduce accumulation of neurotoxic misfolded ⍺-synuclein protein. C57Bl/6 mice were exposed to 2.5 mg/kg/day rotenone by intraperitoneal injection for 14 days. Upon completion of rotenone dosing, mice were orally treated at day 15 with 30 mg/kg/day or 100 mg/kg/day PT150 in the 14-day post-lesioning incubation period, during which the majority of DAn loss and α-synuclein (α-syn) accumulation occurs. Our results indicate that treatment with PT150 reduced both loss of DAn and microgliosis in the nigrostriatal pathway. Although morphologic features of astrogliosis were not attenuated, PT150 treatment promoted potentially neuroprotective activity in these cells, including increased phagocytosis of hyperphosphorylated α-syn. Ultimately, PT150 treatment reduced the loss of DAn cell bodies in the SN, but not the striatum, and prohibited intra-neuronal accumulation of α-syn. Together, these data indicate that PT150 effectively reduced SN pathology in the rotenone mouse model of PD.
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Affiliation(s)
- Amanda S Latham
- Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, CO 80523, United States
| | - Savannah M Rocha
- Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, CO 80523, United States
| | - Casey P McDermott
- Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, CO 80523, United States
| | - Philip Reigan
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
| | - Richard A Slayden
- Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO 80523, United States
| | - Ronald B Tjalkens
- Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, CO 80523, United States.
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Latham AS, Rocha SM, McDermott CP, Reigan P, Slayden RA, Tjalkens RB. Neuroprotective Efficacy of the Glucocorticoid Receptor Modulator PT150 in the Rotenone Mouse Model of Parkinson's Disease. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.04.12.589261. [PMID: 38659796 PMCID: PMC11042181 DOI: 10.1101/2024.04.12.589261] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/26/2024]
Abstract
Parkinson's disease (PD) is the most common neurodegenerative movement disorder worldwide. Current treatments for PD largely center around dopamine replacement therapies and fail to prevent the progression of pathology, underscoring the need for neuroprotective interventions. Approaches that target neuroinflammation, which occurs prior to dopaminergic neuron (DAn) loss in the substantia nigra (SN), represent a promising therapeutic strategy. The glucocorticoid receptor (GR) has been implicated in the neuropathology of PD and modulates numerous neuroinflammatory signaling pathways in the brain. Therefore, we investigated the neuroprotective effects of the novel GR modulator, PT150, in the rotenone mouse model of PD, postulating that inhibition of glial inflammation would protect DAn and reduce accumulation of neurotoxic misfolded ⍺-synuclein protein. C57Bl/6 mice were exposed to 2.5 mg/kg/day rotenone by intraperitoneal injection for 14 days, immediately followed by oral treatment with 30 mg/kg/day or 100 mg/kg/day PT150 in the 14-day post-lesioning incubation period, during which the majority of DAn loss and α-synuclein (α-syn) accumulation occurs. Our results indicate that treatment with PT150 reduced both loss of DAn and microgliosis in the nigrostriatal pathway. Although morphologic features of astrogliosis were not attenuated, PT150 treatment promoted potentially neuroprotective activity in these cells, including increased phagocytosis of hyperphosphorylated α-syn. Ultimately, PT150 treatment reduced the loss of DAn cell bodies in the SN, but not the striatum, and prohibited intra-neuronal accumulation of α-syn. Together, these data indicate that PT150 effectively reduced SN pathology in the rotenone mouse model of PD.
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Gence L, Fernezelian D, Meilhac O, Rastegar S, Bascands JL, Diotel N. Insulin signaling promotes neurogenesis in the brain of adult zebrafish. J Comp Neurol 2023; 531:1812-1827. [PMID: 37750011 DOI: 10.1002/cne.25542] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2023] [Revised: 06/20/2023] [Accepted: 09/08/2023] [Indexed: 09/27/2023]
Abstract
Insulin is a peptide hormone that plays a central role in the regulation of circulating blood glucose in vertebrates, including zebrafish. Increasing evidence has demonstrated the important role of insulin in many brain functions. In zebrafish, two insulin receptor genes (insra and insrb) have been identified. However, their biodistribution in the adult brain as well as their cell-specific expression pattern has not been well described. Using gene expression analysis, in situ hybridization and transgenic fish, we confirmed the expression of insra, insrb, and irs1 (insulin receptor substrate 1, the downstream effector of insulin receptor) in the brain of adult zebrafish and characterized their specific expression in neurons and neural stem cells (radial glia). After demonstrating that intracerebroventricular (ICV) injection resulted in the diffusion of the injected solution within the ventricular system, we analyzed the effect of insulin ICV injection on neurogenesis. We showed that insulin promotes ventricular cell proliferation 24 h postinjection. This neurogenic effect appeared to be independent of neuroinflammatory processes. Also, after a mechanical telencephalic stab-wound injury, we highlighted the overexpression of irs1 gene 5 days postlesion notably in the ventricular zone where radial glial cells (RGCs) are localized, suggesting key roles of insulin signaling in regenerative processes. Finally, our results reinforced the expression of insulin-related proteins in the brain of adult zebrafish, highlighting the potential role of insulin signaling on neurogenesis.
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Affiliation(s)
- Laura Gence
- Université de La Réunion, INSERM, UMR 1188, Diabète athérothrombose Thérapies Réunion Océan Indien (DéTROI), Saint-Denis, La Réunion, France
| | - Danielle Fernezelian
- Université de La Réunion, INSERM, UMR 1188, Diabète athérothrombose Thérapies Réunion Océan Indien (DéTROI), Saint-Denis, La Réunion, France
| | - Olivier Meilhac
- Université de La Réunion, INSERM, UMR 1188, Diabète athérothrombose Thérapies Réunion Océan Indien (DéTROI), Saint-Denis, La Réunion, France
- CHU de La Réunion, Saint-Denis, La Réunion, France
| | - Sepand Rastegar
- Institute of Biological and Chemical Systems-Biological Information Processing (IBCS-BIP), Karlsruhe Institute of Technology (KIT), Karlsruhe, Germany
| | - Jean-Loup Bascands
- Université de La Réunion, INSERM, UMR 1188, Diabète athérothrombose Thérapies Réunion Océan Indien (DéTROI), Saint-Denis, La Réunion, France
| | - Nicolas Diotel
- Université de La Réunion, INSERM, UMR 1188, Diabète athérothrombose Thérapies Réunion Océan Indien (DéTROI), Saint-Denis, La Réunion, France
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7
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Palsamy K, Chen JY, Skaggs K, Qadeer Y, Connors M, Cutler N, Richmond J, Kommidi V, Poles A, Affrunti D, Powell C, Goldman D, Parent JM. Microglial depletion after brain injury prolongs inflammation and impairs brain repair, adult neurogenesis and pro-regenerative signaling. Glia 2023; 71:2642-2663. [PMID: 37449457 PMCID: PMC10528132 DOI: 10.1002/glia.24444] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2023] [Revised: 06/28/2023] [Accepted: 06/30/2023] [Indexed: 07/18/2023]
Abstract
The adult zebrafish brain, unlike mammals, has a remarkable regenerative capacity. Although inflammation in part hinders regeneration in mammals, it is necessary for zebrafish brain repair. Microglia are resident brain immune cells that regulate the inflammatory response. To explore the microglial role in repair, we used liposomal clodronate or colony stimulating factor-1 receptor (csf1r) inhibitor to suppress microglia after brain injury, and also examined regeneration in two genetic mutant lines that lack microglia. We found that microglial ablation impaired telencephalic regeneration after injury. Microglial suppression attenuated cell proliferation at the intermediate progenitor cell amplification stage of neurogenesis. Notably, the loss of microglia impaired phospho-Stat3 (signal transducer and activator of transcription 3) and ß-Catenin signaling after injury. Furthermore, the ectopic activation of Stat3 and ß-Catenin rescued neurogenesis defects caused by microglial loss. Microglial suppression also prolonged the post-injury inflammatory phase characterized by neutrophil accumulation, likely hindering the resolution of inflammation. These findings reveal specific roles of microglia and inflammatory signaling during zebrafish telencephalic regeneration that should advance strategies to improve mammalian brain repair.
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Affiliation(s)
- Kanagaraj Palsamy
- Department of Neurology, University of Michigan, Ann Arbor, Michigan, USA
| | - Jessica Y Chen
- Department of Neurology, University of Michigan, Ann Arbor, Michigan, USA
| | - Kaia Skaggs
- Department of Neurology, University of Michigan, Ann Arbor, Michigan, USA
- University of Findlay, Findlay, Ohio, USA
| | - Yusuf Qadeer
- Department of Neurology, University of Michigan, Ann Arbor, Michigan, USA
| | - Meghan Connors
- Department of Neurology, University of Michigan, Ann Arbor, Michigan, USA
| | - Noah Cutler
- Department of Neurology, University of Michigan, Ann Arbor, Michigan, USA
| | - Joshua Richmond
- Department of Neurology, University of Michigan, Ann Arbor, Michigan, USA
| | - Vineeth Kommidi
- Department of Neurology, University of Michigan, Ann Arbor, Michigan, USA
| | - Allison Poles
- Department of Neurology, University of Michigan, Ann Arbor, Michigan, USA
| | - Danielle Affrunti
- Department of Neurology, University of Michigan, Ann Arbor, Michigan, USA
| | - Curtis Powell
- Michigan Neuroscience Institute, Ann Arbor, Michigan, USA
- Department of Biological Chemistry, University of Michigan, Ann Arbor, Michigan, USA
| | - Daniel Goldman
- Michigan Neuroscience Institute, Ann Arbor, Michigan, USA
- Department of Biological Chemistry, University of Michigan, Ann Arbor, Michigan, USA
| | - Jack M Parent
- Department of Neurology, University of Michigan, Ann Arbor, Michigan, USA
- Michigan Neuroscience Institute, Ann Arbor, Michigan, USA
- VA Ann Arbor Healthcare System, Ann Arbor, Michigan, USA
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Razmara P, Pyle GG. Impact of Copper Nanoparticles and Copper Ions on Transcripts Involved in Neural Repair Mechanisms in Rainbow Trout Olfactory Mucosa. ARCHIVES OF ENVIRONMENTAL CONTAMINATION AND TOXICOLOGY 2023; 84:18-31. [PMID: 36525054 DOI: 10.1007/s00244-022-00969-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Accepted: 11/22/2022] [Indexed: 06/17/2023]
Abstract
Olfactory mucosa is well known for its lifelong ability for regeneration. Regeneration of neurons and regrowth of severed axons are the most common neural repair mechanisms in olfactory mucosa. Nonetheless, exposure to neurotoxic contaminants, such as copper nanoparticles (CuNPs) and copper ions (Cu2+), may alter the reparative capacity of olfactory mucosa. Here, using RNA-sequencing, we investigated the molecular basis of neural repair mechanisms that were affected by CuNPs and Cu2+ in rainbow trout olfactory mucosa. The transcript profile of olfactory mucosa suggested that regeneration of neurons was inhibited by CuNPs. Exposure to CuNPs reduced the transcript abundances of pro-inflammatory proteins which are required to initiate neuroregeneration. Moreover, the transcript of genes encoding regeneration promoters, including canonical Wnt/β-catenin signaling proteins and developmental transcription factors, were downregulated in the CuNP-treated fish. The mRNA levels of genes regulating axonal regrowth, including the growth-promoting signals secreted from olfactory ensheathing cells, were mainly increased in the CuNP treatment. However, the reduced transcript abundances of a few cell adhesion molecules and neural polarity genes may restrict axonogenesis in the CuNP-exposed olfactory mucosa. In the Cu2+-treated olfactory mucosa, both neural repair strategies were initiated at the transcript level. The stimulation of repair mechanisms can lead to the recovery of Cu2+-induced olfactory dysfunction. These results indicated CuNPs and Cu2+ differentially affected the neural repair mechanism in olfactory mucosa. Exposure to CuNP had greater effects on the expression of genes involved in olfactory repair mechanisms relative to Cu2+ and dysregulated the transcripts associated with stem cell proliferation and neural reconstitution.
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Affiliation(s)
- Parastoo Razmara
- Department of Biological Sciences, University of Lethbridge, Lethbridge, AB, Canada.
- Department of Biological Sciences, University of Alberta, Edmonton, AB, Canada.
| | - Gregory G Pyle
- Department of Biological Sciences, University of Lethbridge, Lethbridge, AB, Canada
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Zhuang J, Chen P, Wu Y, Luo Q, Wang Q, Chen S, Chen X, Jiang Z, Qiu J, Li Y, Yuan Z, Zhuang J. Brca1 Is Regulated by the Transcription Factor Gata3, and Its Silencing Promotes Neural Differentiation in Retinal Neurons. Int J Mol Sci 2022; 23:ijms232213860. [PMID: 36430332 PMCID: PMC9694312 DOI: 10.3390/ijms232213860] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2022] [Revised: 10/29/2022] [Accepted: 11/03/2022] [Indexed: 11/12/2022] Open
Abstract
Previous studies have indicated that Brca1 (Breast cancer suppressor gene 1) plays an important role in neural development and degenerative diseases. However, the bioactivity and regulatory mechanism of Brca1 expression in retinal neurocytes remain unclear. In the present study, our data indicated that Brca1 maintains the state of neuronal precursor cells. Brca1 silencing induces differentiation in 661W cells. Nestin, a marker of precursor cells, was significantly decreased in parallel with Brca1 silencing in 661W cells, whereas Map2 (Microtubule associated protein 2), a marker of differentiated neurons, was significantly increased. Neurite outgrowth was increased by ~4.0-fold in Brca1-silenced cells. Moreover, DNA affinity purification assays and ChIP assays demonstrated that Gata3 (GATA binding protein 3) regulates Brca1 transcription in 661W cells. Silencing or overexpressing Gata3 could significantly regulate the expression of Brca1 and affect its promoter inducibility. Furthermore, the expression of Gata3 generally occurred in parallel with that of Brca1 in developing mouse retinas. Both Gata3 and Brca1 are expressed in the neonatal mouse retina but are developmentally silenced with age. Exogenous Gata3 significantly inhibited neural activity by decreasing synaptophysin and neurite outgrowth. Thus, this study demonstrated that Brca1 is transcriptionally regulated by Gata3. Brca1/Gata3 silencing is involved in neuronal differentiation and maturation.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | - Zhaohui Yuan
- Correspondence: (Z.Y.); (J.Z.); Tel.: +86-20-6667-8735 (J.Z.); Fax: +86-20-8733-3271 (J.Z.)
| | - Jing Zhuang
- Correspondence: (Z.Y.); (J.Z.); Tel.: +86-20-6667-8735 (J.Z.); Fax: +86-20-8733-3271 (J.Z.)
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Ilie OD, Duta R, Balmus IM, Savuca A, Petrovici A, Nita IB, Antoci LM, Jijie R, Mihai CT, Ciobica A, Nicoara M, Popescu R, Dobrin R, Solcan C, Trifan A, Stanciu C, Doroftei B. Assessing the Neurotoxicity of a Sub-Optimal Dose of Rotenone in Zebrafish ( Danio rerio) and the Possible Neuroactive Potential of Valproic Acid, Combination of Levodopa and Carbidopa, and Lactic Acid Bacteria Strains. Antioxidants (Basel) 2022; 11:2040. [PMID: 36290763 PMCID: PMC9598446 DOI: 10.3390/antiox11102040] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2022] [Revised: 10/03/2022] [Accepted: 10/13/2022] [Indexed: 11/20/2022] Open
Abstract
Parkinson's disease (PD) is an enigmatic neurodegenerative disorder that is currently the subject of extensive research approaches aiming at deepening the understanding of its etiopathophysiology. Recent data suggest that distinct compounds used either as anticonvulsants or agents usually used as dopaminergic agonists or supplements consisting of live active lactic acid bacteria strains might alleviate and improve PD-related phenotypes. This is why we aimed to elucidate how the administration of rotenone (ROT) disrupts homeostasis and the possible neuroactive potential of valproic acid (VPA), antiparkinsonian agents (levodopa and carbidopa - LEV+CARB), and a mixture of six Lactobacillus and three Bifidobacterium species (PROBIO) might re-establish the optimal internal parameters. ROT causes significant changes in the central nervous system (CNS), notably reduced neurogenesis and angiogenesis, by triggering apoptosis, reflected by the increased expression of PARKIN and PINK1 gene(s), low brain dopamine (DA) levels, and as opposed to LRRK2 and SNCA compared with healthy zebrafish. VPA, LEV/CARB, and PROBIO sustain neurogenesis and angiogenesis, manifesting a neuroprotective role in diminishing the effect of ROT in zebrafish. Interestingly, none of the tested compounds influenced oxidative stress (OS), as reflected by the level of malondialdehyde (MDA) level and superoxide dismutase (SOD) enzymatic activity revealed in non-ROT-exposed zebrafish. Overall, the selected concentrations were enough to trigger particular behavioral patterns as reflected by our parameters of interest (swimming distance (mm), velocity (mm/s), and freezing episodes (s)), but sequential testing is mandatory to decipher whether they exert an inhibitory role following ROT exposure. In this way, we further offer data into how ROT may trigger a PD-related phenotype and the possible beneficial role of VPA, LEV+CARB, and PROBIO in re-establishing homeostasis in Danio rerio.
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Affiliation(s)
- Ovidiu-Dumitru Ilie
- Department of Biology, Faculty of Biology, “Alexandru Ioan Cuza” University, Carol I Avenue, no 20A, 700505 Iasi, Romania
| | - Raluca Duta
- Department of Biology, Faculty of Biology, “Alexandru Ioan Cuza” University, Carol I Avenue, no 20A, 700505 Iasi, Romania
| | - Ioana-Miruna Balmus
- Department of Exact and Natural Sciences, Institute of Interdisciplinary Research, “Alexandru Ioan Cuza” University, Carol I Avenue, no 11, 700506 Iasi, Romania
- Doctoral School of Biology, Faculty of Biology, “Alexandru Ioan Cuza” University, Carol I Avenue, 20A, 700506 Iasi, Romania
| | - Alexandra Savuca
- Doctoral School of Geosciences, Faculty of Geography-Geology, “Alexandru Ioan Cuza” University, Carol I Avenue, no 20A, 700505 Iasi, Romania
| | - Adriana Petrovici
- Department of Molecular Biology, Histology and Embryology, Faculty of Veterinary Medicine, University of Life Sciences “Ion Ionescu de la Brad”, Mihail Sadoveanu Street, no 3, 700490 Iasi, Romania
| | - Ilinca-Bianca Nita
- Faculty of Medicine, University of Medicine and Pharmacy “Grigore T. Popa”, University Street, no 16, 700115 Iasi, Romania
| | - Lucian-Mihai Antoci
- Department of Medical Genetics, University of Medicine and Pharmacy “Grigore T. Popa”, University Street, no 16, 700115 Iasi, Romania
| | - Roxana Jijie
- Research Center on Advanced Materials and Technologies, Department of Exact and Natural Sciences, Institute of Inderdisciplinary Research, “Alexandru Ioan Cuza” University, Carol I Avenue, no 11, 700506 Iasi, Romania
| | - Cosmin-Teodor Mihai
- Advanced Research and Development Center for Experimental Medicine (CEMEX), University of Medicine and Pharmacy “Grigore T. Popa”, University Street, no 16, 700115 Iasi, Romania
| | - Alin Ciobica
- Department of Biology, Faculty of Biology, “Alexandru Ioan Cuza” University, Carol I Avenue, no 20A, 700505 Iasi, Romania
| | - Mircea Nicoara
- Department of Biology, Faculty of Biology, “Alexandru Ioan Cuza” University, Carol I Avenue, no 20A, 700505 Iasi, Romania
- Doctoral School of Geosciences, Faculty of Geography-Geology, “Alexandru Ioan Cuza” University, Carol I Avenue, no 20A, 700505 Iasi, Romania
| | - Roxana Popescu
- Department of Medical Genetics, University of Medicine and Pharmacy “Grigore T. Popa”, University Street, no 16, 700115 Iasi, Romania
- Department of Medical Genetics, “Saint Mary” Emergency Children’s Hospital, Vasile Lupu Street, no 62, 700309 Iasi, Romania
| | - Romeo Dobrin
- Department of Psychiatry, University of Medicine and Pharmacy “Grigore T. Popa”, University Street, no 16, 700115 Iasi, Romania
| | - Carmen Solcan
- Department of Molecular Biology, Histology and Embryology, Faculty of Veterinary Medicine, University of Life Sciences “Ion Ionescu de la Brad”, Mihail Sadoveanu Street, no 3, 700490 Iasi, Romania
| | - Anca Trifan
- Department of Gastroenterology, University of Medicine and Pharmacy “Grigore T. Popa”, University Street, no 16, 700115 Iasi, Romania
- Institute of Gastroenterology and Hepatology, “St. Spiridon” Emergency Hospital, Independence Avenue, no 1, 700111 Iasi, Romania
| | - Carol Stanciu
- Department of Gastroenterology, University of Medicine and Pharmacy “Grigore T. Popa”, University Street, no 16, 700115 Iasi, Romania
- Institute of Gastroenterology and Hepatology, “St. Spiridon” Emergency Hospital, Independence Avenue, no 1, 700111 Iasi, Romania
| | - Bogdan Doroftei
- Faculty of Medicine, University of Medicine and Pharmacy “Grigore T. Popa”, University Street, no 16, 700115 Iasi, Romania
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11
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Zou D, Qin J, Hu W, Wei Z, Zhan Y, He Y, Zhao C, Li L. Macrophages Rapidly Seal off the Punctured Zebrafish Larval Brain through a Vital Honeycomb Network Structure. Int J Mol Sci 2022; 23:ijms231810551. [PMID: 36142462 PMCID: PMC9503817 DOI: 10.3390/ijms231810551] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Revised: 08/30/2022] [Accepted: 09/07/2022] [Indexed: 11/26/2022] Open
Abstract
There is accumulating evidence that macrophages play additional important roles in tissue damage besides their typical phagocytosis. Although the aggregation of macrophages on injured sites has long been observed, few researchers have focused on the role of the overall structure of macrophage aggregation. In this study, we developed a standardized traumatic brain injury (TBI) model in zebrafish larvae to mimic edema and brain tissue spillage symptoms after severe brain trauma. Using time-lapse imaging, we showed that macrophages/microglia in zebrafish larvae responded rapidly and dominated the surface of injured tissue, forming a meaningful honeycomb network structure through their compact aggregation and connection. Disrupting this structure led to fatal edema-like symptoms with severe loss of brain tissue. Using the RNA-Seq, together with the manipulation of in vitro cell lines, we found that collagen IV was indispensable to the formation of honeycomb network structures. Our study thus revealed a novel perspective regarding macrophages forming a protective compact structure with collagen IV. This honeycomb network structure acted as a physical barrier to prevent tissue loss and maintain brain homeostasis after TBI. This study may provide new evidence of macrophages’ function for the rapid protection of brain tissue after brain injury.
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Affiliation(s)
- Dandan Zou
- Key Laboratory of Freshwater Fish Reproduction and Development, Ministry of Education, Institute of Developmental Biology and Regenerative Medicine, Southwest University, Beibei, Chongqing 400715, China
| | - Jie Qin
- Key Laboratory of Freshwater Fish Reproduction and Development, Ministry of Education, Institute of Developmental Biology and Regenerative Medicine, Southwest University, Beibei, Chongqing 400715, China
| | - Wenlong Hu
- Key Laboratory of Freshwater Fish Reproduction and Development, Ministry of Education, Institute of Developmental Biology and Regenerative Medicine, Southwest University, Beibei, Chongqing 400715, China
| | - Zongfang Wei
- Key Laboratory of Freshwater Fish Reproduction and Development, Ministry of Education, Institute of Developmental Biology and Regenerative Medicine, Southwest University, Beibei, Chongqing 400715, China
| | - Yandong Zhan
- Key Laboratory of Freshwater Fish Reproduction and Development, Ministry of Education, Institute of Developmental Biology and Regenerative Medicine, Southwest University, Beibei, Chongqing 400715, China
| | - Yuepeng He
- Key Laboratory of Freshwater Fish Reproduction and Development, Ministry of Education, Institute of Developmental Biology and Regenerative Medicine, Southwest University, Beibei, Chongqing 400715, China
| | - Congjian Zhao
- Chongqing Engineering Research Center of Medical Electronics and Information Technology, School of Biomedical Engineering and Informatics, Chongqing University of Posts and Telecommunications, Chongqing 400065, China
| | - Li Li
- Research Center of Stem Cells and Ageing, Chongqing Institute of Green and Intelligent Technology, Chinese Academy of Sciences, Chongqing 400714, China
- Correspondence:
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12
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Wei X, Fu S, Li H, Liu Y, Wang S, Feng W, Yang Y, Liu X, Zeng YY, Cheng M, Lai Y, Qiu X, Wu L, Zhang N, Jiang Y, Xu J, Su X, Peng C, Han L, Lou WPK, Liu C, Yuan Y, Ma K, Yang T, Pan X, Gao S, Chen A, Esteban MA, Yang H, Wang J, Fan G, Liu L, Chen L, Xu X, Fei JF, Gu Y. Single-cell Stereo-seq reveals induced progenitor cells involved in axolotl brain regeneration. Science 2022; 377:eabp9444. [PMID: 36048929 DOI: 10.1126/science.abp9444] [Citation(s) in RCA: 102] [Impact Index Per Article: 34.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
The molecular mechanism underlying brain regeneration in vertebrates remains elusive. We performed spatial enhanced resolution omics sequencing (Stereo-seq) to capture spatially resolved single-cell transcriptomes of axolotl telencephalon sections during development and regeneration. Annotated cell types exhibited distinct spatial distribution, molecular features, and functions. We identified an injury-induced ependymoglial cell cluster at the wound site as a progenitor cell population for the potential replenishment of lost neurons, through a cell state transition process resembling neurogenesis during development. Transcriptome comparisons indicated that these induced cells may originate from local resident ependymoglial cells. We further uncovered spatially defined neurons at the lesion site that may regress to an immature neuron-like state. Our work establishes spatial transcriptome profiles of an anamniote tetrapod brain and decodes potential neurogenesis from ependymoglial cells for development and regeneration, thus providing mechanistic insights into vertebrate brain regeneration.
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Affiliation(s)
- Xiaoyu Wei
- BGI-Hangzhou, Hangzhou 310012, China.,BGI-Shenzhen, Shenzhen 518103, China
| | - Sulei Fu
- Department of Pathology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, China.,Key Laboratory of Brain, Cognition and Education Sciences, Ministry of Education, Institute for Brain Research and Rehabilitation, South China Normal University, Guangzhou 510631, China
| | - Hanbo Li
- BGI-Shenzhen, Shenzhen 518103, China.,BGI-Qingdao, Qingdao 266555, China.,Lars Bolund Institute of Regenerative Medicine, Qingdao-Europe Advanced Institute for Life Sciences, BGI-Qingdao, Qingdao 266555, China
| | - Yang Liu
- BGI-Shenzhen, Shenzhen 518103, China
| | - Shuai Wang
- BGI-Shenzhen, Shenzhen 518103, China.,College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China
| | - Weimin Feng
- BGI-Shenzhen, Shenzhen 518103, China.,College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China
| | - Yunzhi Yang
- BGI College & Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450000, China
| | | | - Yan-Yun Zeng
- Department of Pathology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, China.,Key Laboratory of Brain, Cognition and Education Sciences, Ministry of Education, Institute for Brain Research and Rehabilitation, South China Normal University, Guangzhou 510631, China
| | - Mengnan Cheng
- BGI-Shenzhen, Shenzhen 518103, China.,College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China
| | - Yiwei Lai
- Laboratory of Integrative Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
| | - Xiaojie Qiu
- Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.,Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
| | - Liang Wu
- BGI-Shenzhen, Shenzhen 518103, China.,College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China
| | | | - Yujia Jiang
- BGI-Shenzhen, Shenzhen 518103, China.,BGI College & Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450000, China
| | - Jiangshan Xu
- BGI-Shenzhen, Shenzhen 518103, China.,College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China
| | | | - Cheng Peng
- Department of Pathology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, China.,Key Laboratory of Brain, Cognition and Education Sciences, Ministry of Education, Institute for Brain Research and Rehabilitation, South China Normal University, Guangzhou 510631, China
| | - Lei Han
- BGI-Shenzhen, Shenzhen 518103, China.,Shenzhen Key Laboratory of Single-Cell Omics, BGI-Shenzhen, Shenzhen 518120, China.,Shenzhen Bay Laboratory, Shenzhen 518000, China
| | - Wilson Pak-Kin Lou
- Department of Pathology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, China.,Key Laboratory of Brain, Cognition and Education Sciences, Ministry of Education, Institute for Brain Research and Rehabilitation, South China Normal University, Guangzhou 510631, China
| | - Chuanyu Liu
- BGI-Shenzhen, Shenzhen 518103, China.,Shenzhen Bay Laboratory, Shenzhen 518000, China
| | - Yue Yuan
- BGI-Shenzhen, Shenzhen 518103, China.,College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China
| | | | - Tao Yang
- BGI-Shenzhen, Shenzhen 518103, China
| | - Xiangyu Pan
- Department of Pathology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, China
| | | | - Ao Chen
- BGI-Shenzhen, Shenzhen 518103, China.,Department of Biology, University of Copenhagen, Copenhagen DK-2200, Denmark
| | - Miguel A Esteban
- Laboratory of Integrative Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.,Institute of Stem Cells and Regeneration, Chinese Academy of Sciences, Beijing 100101, China
| | - Huanming Yang
- BGI-Shenzhen, Shenzhen 518103, China.,James D. Watson Institute of Genome Sciences, Hangzhou 310058, China
| | - Jian Wang
- BGI-Shenzhen, Shenzhen 518103, China.,James D. Watson Institute of Genome Sciences, Hangzhou 310058, China
| | | | - Longqi Liu
- BGI-Hangzhou, Hangzhou 310012, China.,BGI-Shenzhen, Shenzhen 518103, China.,College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China.,Shenzhen Bay Laboratory, Shenzhen 518000, China
| | - Liang Chen
- Hubei Key Laboratory of Cell Homeostasis, RNA Institute, College of Life Sciences, Wuhan University, Wuhan 430072, China
| | - Xun Xu
- BGI-Shenzhen, Shenzhen 518103, China.,Guangdong Provincial Key Laboratory of Genome Read and Write, BGI-Shenzhen, Shenzhen 518120, China
| | - Ji-Feng Fei
- Department of Pathology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, China
| | - Ying Gu
- BGI-Hangzhou, Hangzhou 310012, China.,BGI-Shenzhen, Shenzhen 518103, China.,College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China.,Guangdong Provincial Key Laboratory of Genome Read and Write, BGI-Shenzhen, Shenzhen 518120, China
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13
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Caron A, Trzuskot L, Lindsey BW. Uncovering the spectrum of adult zebrafish neural stem cell cycle regulators. Front Cell Dev Biol 2022; 10:941893. [PMID: 35846369 PMCID: PMC9277145 DOI: 10.3389/fcell.2022.941893] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Accepted: 06/16/2022] [Indexed: 11/13/2022] Open
Abstract
Adult neural stem and progenitor cells (aNSPCs) persist lifelong in teleost models in diverse stem cell niches of the brain and spinal cord. Fish maintain developmental stem cell populations throughout life, including both neuro-epithelial cells (NECs) and radial-glial cells (RGCs). Within stem cell domains of the brain, RGCs persist in a cycling or quiescent state, whereas NECs continuously divide. Heterogeneous populations of RGCs also sit adjacent the central canal of the spinal cord, showing infrequent proliferative activity under homeostasis. With the rise of the zebrafish (Danio rerio) model to study adult neurogenesis and neuroregeneration in the central nervous system (CNS), it has become evident that aNSPC proliferation is regulated by a wealth of stimuli that may be coupled with biological function. Growing evidence suggests that aNSPCs are sensitive to environmental cues, social interactions, nutrient availability, and neurotrauma for example, and that distinct stem and progenitor cell populations alter their cell cycle activity accordingly. Such stimuli appear to act as triggers to either turn on normally dormant aNSPCs or modulate constitutive rates of niche-specific cell cycle behaviour. Defining the various forms of stimuli that influence RGC and NEC proliferation, and identifying the molecular regulators responsible, will strengthen our understanding of the connection between aNSPC activity and their biological significance. In this review, we aim to bring together the current state of knowledge on aNSPCs from studies investigating the zebrafish CNS, while highlighting emerging cell cycle regulators and outstanding questions that will help to advance this fascinating field of stem cell biology.
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Affiliation(s)
- Aurélien Caron
- Laboratory of Neural Stem Cell Plasticity and Regeneration, Department of Human Anatomy and Cell Science, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada
| | - Lidia Trzuskot
- Laboratory of Neural Stem Cell Plasticity and Regeneration, Department of Human Anatomy and Cell Science, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada
| | - Benjamin W Lindsey
- Laboratory of Neural Stem Cell Plasticity and Regeneration, Department of Human Anatomy and Cell Science, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada
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14
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Kizil C, Sariya S, Kim YA, Rajabli F, Martin E, Reyes-Dumeyer D, Vardarajan B, Maldonado A, Haines JL, Mayeux R, Jiménez-Velázquez IZ, Santa-Maria I, Tosto G. Admixture Mapping of Alzheimer's disease in Caribbean Hispanics identifies a new locus on 22q13.1. Mol Psychiatry 2022; 27:2813-2820. [PMID: 35365809 PMCID: PMC9167722 DOI: 10.1038/s41380-022-01526-6] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2021] [Revised: 02/28/2022] [Accepted: 03/14/2022] [Indexed: 11/09/2022]
Abstract
Late-onset Alzheimer's disease (LOAD) is significantly more frequent in Hispanics than in non-Hispanic Whites. Ancestry may explain these differences across ethnic groups. To this end, we studied a large cohort of Caribbean Hispanics (CH, N = 8813) and tested the association between Local Ancestry (LA) and LOAD ("admixture mapping") to identify LOAD-associated ancestral blocks, separately for ancestral components (European [EUR], African [AFR], Native American[NA]) and jointly (AFR + NA). Ancestral blocks significant after permutation were fine-mapped employing multi-ethnic whole-exome sequencing (WES) to identify rare variants associated with LOAD (SKAT-O) and replicated in the UK Biobank WES dataset. Candidate genes were validated studying (A) protein expression in human LOAD and control brains; (B) two animal AD models, Drosophila and Zebrafish. In the joint AFR + NA model, we identified four significant ancestral blocks located on chromosomes 1 (p value = 8.94E-05), 6 (p value = 8.63E-05), 21 (p value = 4.64E-05) and 22 (p value = 1.77E-05). Fine-mapping prioritized the GCAT gene on chromosome 22 (SKAT-O p value = 3.45E-05) and replicated in the UK Biobank (SKAT-O p value = 0.05). In LOAD brains, a decrease of 28% in GCAT protein expression was observed (p value = 0.038), and GCAT knockdown in Amyloid-β42 Drosophila exacerbated rough eye phenotype (68% increase, p value = 4.84E-09). In zebrafish, gcat expression increased after acute amyloidosis (34%, p value = 0.0049), and decreased upon anti-inflammatory Interleukin-4 (39%, p value = 2.3E-05). Admixture mapping uncovered genomic regions harboring new LOAD-associated loci that might explain the observed different frequency of LOAD across ethnic groups. Our results suggest that the inflammation-related activity of GCAT is a response to amyloid toxicity, and reduced GCAT expression exacerbates AD pathology.
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Affiliation(s)
- Caghan Kizil
- Taub Institute for Research on Alzheimer's Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University, 630 West168 th Street, New York, NY, 10032, USA
- Department of Neurology, College of Physicians and Surgeons, Columbia University and the New York Presbyterian Hospital, 710 West 168th Street, New York, NY, 10032, USA
- German Center for Neurodegenerative Diseases (DZNE), Helmholtz Association, Tatzberg 41, 01307, Dresden, Germany
| | - Sanjeev Sariya
- Taub Institute for Research on Alzheimer's Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University, 630 West168 th Street, New York, NY, 10032, USA
- Department of Neurology, College of Physicians and Surgeons, Columbia University and the New York Presbyterian Hospital, 710 West 168th Street, New York, NY, 10032, USA
- The Gertrude H. Sergievsky Center, College of Physicians and Surgeons, Columbia University, 630 West 168th Street, New York, NY, 10032, USA
| | - Yoon A Kim
- Taub Institute for Research on Alzheimer's Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University, 630 West168 th Street, New York, NY, 10032, USA
- Department of Pathology & Cell Biology, Columbia University, New York, NY, USA
| | - Farid Rajabli
- John P. Hussman Institute for Human Genomics, University of Miami, Miami, FL, USA
| | - Eden Martin
- John P. Hussman Institute for Human Genomics, University of Miami, Miami, FL, USA
- Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami, Miami, FL, USA
| | - Dolly Reyes-Dumeyer
- Taub Institute for Research on Alzheimer's Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University, 630 West168 th Street, New York, NY, 10032, USA
- Department of Neurology, College of Physicians and Surgeons, Columbia University and the New York Presbyterian Hospital, 710 West 168th Street, New York, NY, 10032, USA
- The Gertrude H. Sergievsky Center, College of Physicians and Surgeons, Columbia University, 630 West 168th Street, New York, NY, 10032, USA
| | - Badri Vardarajan
- Taub Institute for Research on Alzheimer's Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University, 630 West168 th Street, New York, NY, 10032, USA
- Department of Neurology, College of Physicians and Surgeons, Columbia University and the New York Presbyterian Hospital, 710 West 168th Street, New York, NY, 10032, USA
- The Gertrude H. Sergievsky Center, College of Physicians and Surgeons, Columbia University, 630 West 168th Street, New York, NY, 10032, USA
| | - Aleyda Maldonado
- Department of Medicine, School of Medicine, Medical Sciences Campus, University of Puerto Rico, San Juan, PR, 00936, USA
| | - Jonathan L Haines
- Department of Population & Quantitative Health Sciences, Cleveland Institute for Computational Biology, Case Western Reserve University, Cleveland, OH, USA
| | - Richard Mayeux
- Taub Institute for Research on Alzheimer's Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University, 630 West168 th Street, New York, NY, 10032, USA
- Department of Neurology, College of Physicians and Surgeons, Columbia University and the New York Presbyterian Hospital, 710 West 168th Street, New York, NY, 10032, USA
- The Gertrude H. Sergievsky Center, College of Physicians and Surgeons, Columbia University, 630 West 168th Street, New York, NY, 10032, USA
- Department of Medicine, College of Physicians and Surgeons, Columbia University, and the New York Presbyterian Hospital, 630 West 168th Street, New York, NY, 10032, USA
- Department of Psychiatry, College of Physicians and Surgeons, Columbia University, 1051 Riverside Drive, New York, NY, 10032, USA
| | - Ivonne Z Jiménez-Velázquez
- Department of Medicine, School of Medicine, Medical Sciences Campus, University of Puerto Rico, San Juan, PR, 00936, USA
| | - Ismael Santa-Maria
- Taub Institute for Research on Alzheimer's Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University, 630 West168 th Street, New York, NY, 10032, USA
- Department of Pathology & Cell Biology, Columbia University, New York, NY, USA
| | - Giuseppe Tosto
- Taub Institute for Research on Alzheimer's Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University, 630 West168 th Street, New York, NY, 10032, USA.
- Department of Neurology, College of Physicians and Surgeons, Columbia University and the New York Presbyterian Hospital, 710 West 168th Street, New York, NY, 10032, USA.
- The Gertrude H. Sergievsky Center, College of Physicians and Surgeons, Columbia University, 630 West 168th Street, New York, NY, 10032, USA.
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15
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Burda JE, O'Shea TM, Ao Y, Suresh KB, Wang S, Bernstein AM, Chandra A, Deverasetty S, Kawaguchi R, Kim JH, McCallum S, Rogers A, Wahane S, Sofroniew MV. Divergent transcriptional regulation of astrocyte reactivity across disorders. Nature 2022; 606:557-564. [PMID: 35614216 PMCID: PMC10027402 DOI: 10.1038/s41586-022-04739-5] [Citation(s) in RCA: 105] [Impact Index Per Article: 35.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2020] [Accepted: 04/07/2022] [Indexed: 01/30/2023]
Abstract
Astrocytes respond to injury and disease in the central nervous system with reactive changes that influence the outcome of the disorder1-4. These changes include differentially expressed genes (DEGs) whose contextual diversity and regulation are poorly understood. Here we combined biological and informatic analyses, including RNA sequencing, protein detection, assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq) and conditional gene deletion, to predict transcriptional regulators that differentially control more than 12,000 DEGs that are potentially associated with astrocyte reactivity across diverse central nervous system disorders in mice and humans. DEGs associated with astrocyte reactivity exhibited pronounced heterogeneity across disorders. Transcriptional regulators also exhibited disorder-specific differences, but a core group of 61 transcriptional regulators was identified as common across multiple disorders in both species. We show experimentally that DEG diversity is determined by combinatorial, context-specific interactions between transcriptional regulators. Notably, the same reactivity transcriptional regulators can regulate markedly different DEG cohorts in different disorders; changes in the access of transcriptional regulators to DNA-binding motifs differ markedly across disorders; and DEG changes can crucially require multiple reactivity transcriptional regulators. We show that, by modulating reactivity, transcriptional regulators can substantially alter disorder outcome, implicating them as therapeutic targets. We provide searchable resources of disorder-related reactive astrocyte DEGs and their predicted transcriptional regulators. Our findings show that transcriptional changes associated with astrocyte reactivity are highly heterogeneous and are customized from vast numbers of potential DEGs through context-specific combinatorial transcriptional-regulator interactions.
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Affiliation(s)
- Joshua E Burda
- Department of Neurobiology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
- Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
- Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
- Center for Neural Science and Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
- Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
| | - Timothy M O'Shea
- Department of Neurobiology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA
| | - Yan Ao
- Department of Neurobiology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA
| | - Keshav B Suresh
- Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA
- Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, CA, USA
- Center for Neural Science and Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA
- Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Shinong Wang
- Department of Neurobiology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA
| | - Alexander M Bernstein
- Department of Neurobiology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA
| | - Ashu Chandra
- Department of Computer Science, University of California Los Angeles, Los Angeles, CA, USA
| | - Sandeep Deverasetty
- Department of Psychiatry, University of California Los Angeles, Los Angeles, CA, USA
- Department of Neurology, University of California Los Angeles, Los Angeles, CA, USA
| | - Riki Kawaguchi
- Department of Psychiatry, University of California Los Angeles, Los Angeles, CA, USA
- Department of Neurology, University of California Los Angeles, Los Angeles, CA, USA
| | - Jae H Kim
- Department of Neurobiology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA
| | - Sarah McCallum
- Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA
- Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, CA, USA
- Center for Neural Science and Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA
- Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Alexandra Rogers
- Department of Neurobiology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA
| | - Shalaka Wahane
- Department of Neurobiology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA
| | - Michael V Sofroniew
- Department of Neurobiology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
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16
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Single Cell/Nucleus Transcriptomics Comparison in Zebrafish and Humans Reveals Common and Distinct Molecular Responses to Alzheimer’s Disease. Cells 2022; 11:cells11111807. [PMID: 35681503 PMCID: PMC9180693 DOI: 10.3390/cells11111807] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2022] [Revised: 05/25/2022] [Accepted: 05/26/2022] [Indexed: 12/21/2022] Open
Abstract
Neurogenesis is significantly reduced in Alzheimer’s disease (AD) and is a potential therapeutic target. Contrary to humans, a zebrafish can regenerate its diseased brain, and thus is ideal for studying neurogenesis. To compare the AD-related molecular pathways between humans and zebrafish, we compared single cell or nuclear transcriptomic data from a zebrafish amyloid toxicity model and its controls (N = 12) with the datasets of two human adult brains (N = 10 and N = 48 (Microglia)), and one fetal brain (N = 10). Approximately 95.4% of the human and zebrafish cells co-clustered. Within each cell type, we identified differentially expressed genes (DEGs), enriched KEGG pathways, and gene ontology terms. We studied synergistic and non-synergistic DEGs to point at either common or uniquely altered mechanisms across species. Using the top DEGs, a high concordance in gene expression changes between species was observed in neuronal clusters. On the other hand, the molecular pathways affected by AD in zebrafish astroglia differed from humans in favor of the neurogenic pathways. The integration of zebrafish and human transcriptomes shows that the zebrafish can be used as a tool to study the cellular response to amyloid proteinopathies. Uniquely altered pathways in zebrafish could highlight the specific mechanisms underlying neurogenesis, which are absent in humans, and could serve as potential candidates for therapeutic developments.
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17
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Reconstruction of regulatory network predicts transcription factors driving the dynamics of zebrafish heart regeneration. Gene X 2022; 819:146242. [PMID: 35114280 DOI: 10.1016/j.gene.2022.146242] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2021] [Revised: 12/21/2021] [Accepted: 01/18/2022] [Indexed: 11/24/2022] Open
Abstract
The limited regenerative capacity in mammals has serious implications for cardiac tissue damage. Meanwhile, zebrafish has a high regenerative capacity, but the regulation of the heart healing process has yet to be elucidated. The dynamic nature of cardiac regeneration requires consideration of the inherent temporal dimension of this process. Here, we conducted a systematic review to find genes that define the regenerative cell state of the zebrafish heart. We then performed an in silico temporal gene regulatory network analysis using transcriptomic data from the zebrafish heart regenerative process obtained from databases. In this analysis, the genes found in the systematic review were used to represent the final cell state of the transition process from a non-regenerative cell state to a regenerative state. We found 135 transcription factors driving the cellular state transition process during zebrafish cardiac regeneration, including Hand2, Nkx2.5, Tbx20, Fosl1, Fosb, Junb, Vdr, Wt1, and Tcf21 previously reported for playing a key role in tissue regeneration. Furthermore, we demonstrate that most regulators are activated in the first days post-injury, indicating that the transition from a non-regenerative to a regenerative state occurs promptly.
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18
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Incomplete Recovery of Zebrafish Retina Following Cryoinjury. Cells 2022; 11:cells11081373. [PMID: 35456052 PMCID: PMC9030934 DOI: 10.3390/cells11081373] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2022] [Revised: 04/11/2022] [Accepted: 04/12/2022] [Indexed: 02/05/2023] Open
Abstract
Zebrafish show an extraordinary potential for regeneration in several organs from fins to central nervous system. Most impressively, the outcome of an injury results in a near perfect regeneration and a full functional recovery. Indeed, among the various injury paradigms previously tested in the field of zebrafish retina regeneration, a perfect layered structure is observed after one month of recovery in most of the reported cases. In this study, we applied cryoinjury to the zebrafish eye. We show that retina exposed to this treatment for one second undergoes an acute damage affecting all retinal cell types, followed by a phase of limited tissue remodeling and regrowth. Surprisingly, zebrafish developed a persistent retinal dysplasia observable through 300 days post-injury. There is no indication of fibrosis during the regeneration period, contrary to the regeneration process after cryoinjury to the zebrafish cardiac ventricle. RNA sequencing analysis of injured retinas at different time points has uncovered enriched processes and a number of potential candidate genes. By means of this simple, time and cost-effective technique, we propose a zebrafish injury model that displays a unique inability to completely recover following focal retinal damage; an outcome that is unreported to our knowledge. Furthermore, RNA sequencing proved to be useful in identifying pathways, which may play a crucial role not only in the regeneration of the retina, but in the first initial step of regeneration, degeneration. We propose that this model may prove useful in comparative and translational studies to examine critical pathways for successful regeneration.
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Becker T, Becker CG. Regenerative neurogenesis: the integration of developmental, physiological and immune signals. Development 2022; 149:275248. [PMID: 35502778 PMCID: PMC9124576 DOI: 10.1242/dev.199907] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
In fishes and salamanders, but not mammals, neural stem cells switch back to neurogenesis after injury. The signalling environment of neural stem cells is strongly altered by the presence of damaged cells and an influx of immune, as well as other, cells. Here, we summarise our recently expanded knowledge of developmental, physiological and immune signals that act on neural stem cells in the zebrafish central nervous system to directly, or indirectly, influence their neurogenic state. These signals act on several intracellular pathways, which leads to changes in chromatin accessibility and gene expression, ultimately resulting in regenerative neurogenesis. Translational approaches in non-regenerating mammals indicate that central nervous system stem cells can be reprogrammed for neurogenesis. Understanding signalling mechanisms in naturally regenerating species show the path to experimentally promoting neurogenesis in mammals.
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Affiliation(s)
- Thomas Becker
- Center for Regenerative Therapies at the TU Dresden, Technische Universität Dresden, 01307 Dresden, Germany.,Centre for Discovery Brain Sciences, University of Edinburgh Medical School, Biomedical Science, Edinburgh, EH16 4SB, Scotland
| | - Catherina G Becker
- Center for Regenerative Therapies at the TU Dresden, Technische Universität Dresden, 01307 Dresden, Germany.,Centre for Discovery Brain Sciences, University of Edinburgh Medical School, Biomedical Science, Edinburgh, EH16 4SB, Scotland
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20
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Stenudd M, Sabelström H, Llorens-Bobadilla E, Zamboni M, Blom H, Brismar H, Zhang S, Basak O, Clevers H, Göritz C, Barnabé-Heider F, Frisén J. Identification of a discrete subpopulation of spinal cord ependymal cells with neural stem cell properties. Cell Rep 2022; 38:110440. [PMID: 35235796 DOI: 10.1016/j.celrep.2022.110440] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2020] [Revised: 11/30/2021] [Accepted: 02/03/2022] [Indexed: 12/14/2022] Open
Abstract
Spinal cord ependymal cells display neural stem cell properties in vitro and generate scar-forming astrocytes and remyelinating oligodendrocytes after injury. We report that ependymal cells are functionally heterogeneous and identify a small subpopulation (8% of ependymal cells and 0.1% of all cells in a spinal cord segment), which we denote ependymal A (EpA) cells, that accounts for the in vitro stem cell potential in the adult spinal cord. After spinal cord injury, EpA cells undergo self-renewing cell division as they give rise to differentiated progeny. Single-cell transcriptome analysis revealed a loss of ependymal cell gene expression programs as EpA cells gained signaling entropy and dedifferentiated to a stem-cell-like transcriptional state after an injury. We conclude that EpA cells are highly differentiated cells that can revert to a stem cell state and constitute a therapeutic target for spinal cord repair.
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Affiliation(s)
- Moa Stenudd
- Department of Cell and Molecular Biology, Karolinska Institutet, 171 77 Stockholm, Sweden
| | - Hanna Sabelström
- Department of Cell and Molecular Biology, Karolinska Institutet, 171 77 Stockholm, Sweden
| | | | - Margherita Zamboni
- Department of Cell and Molecular Biology, Karolinska Institutet, 171 77 Stockholm, Sweden
| | - Hans Blom
- Science for Life Laboratory, Department of Applied Physics, Royal Institute of Technology, 171 21 Solna, Sweden
| | - Hjalmar Brismar
- Science for Life Laboratory, Department of Applied Physics, Royal Institute of Technology, 171 21 Solna, Sweden
| | - Shupei Zhang
- Department of Cell and Molecular Biology, Karolinska Institutet, 171 77 Stockholm, Sweden
| | - Onur Basak
- Hubrecht Institute for Developmental Biology and Stem Cell Research, 3584 CT Utrecht, the Netherlands; University Medical Centre Utrecht, 3584 GC, Utrecht, the Netherlands
| | - Hans Clevers
- Hubrecht Institute for Developmental Biology and Stem Cell Research, 3584 CT Utrecht, the Netherlands; University Medical Centre Utrecht, 3584 GC, Utrecht, the Netherlands
| | - Christian Göritz
- Department of Cell and Molecular Biology, Karolinska Institutet, 171 77 Stockholm, Sweden; Ming Wai Lau Centre for Reparative Medicine, Stockholm Node, Karolinska Institutet, 171 77 Stockholm, Sweden
| | - Fanie Barnabé-Heider
- Department of Cell and Molecular Biology, Karolinska Institutet, 171 77 Stockholm, Sweden; Department of Neuroscience, Karolinska Institutet, 171 77 Stockholm, Sweden
| | - Jonas Frisén
- Department of Cell and Molecular Biology, Karolinska Institutet, 171 77 Stockholm, Sweden.
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21
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Chen P, Wu Y, Zhuang J, Liu X, Luo Q, Wang Q, Jiang Z, He A, Chen S, Chen X, Qiu J, Li Y, Yang Y, Yu K, Zhuang J. Gata3 Silencing Is Involved in Neuronal Differentiation and Its Abnormal Expression Impedes Neural Activity in Adult Retinal Neurocytes. Int J Mol Sci 2022; 23:ijms23052495. [PMID: 35269648 PMCID: PMC8910128 DOI: 10.3390/ijms23052495] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Revised: 02/14/2022] [Accepted: 02/18/2022] [Indexed: 12/10/2022] Open
Abstract
GATA binding protein 3 (Gata3), a zinc-finger transcription factor, plays an important role in neural development. However, its expression and bioactivity in the retina remain unclear. In the present study, our data indicated that Gata3 maintains the precursor state of 661W cells, and Gata3 silencing induces cell differentiation. The expression of Nestin, a marker of precursor cells, was significantly decreased in parallel, whereas the expression of Map2, a marker of differentiated neurons, was significantly increased following the decrease in Gata3. Neurite outgrowth was increased by 2.78-fold in Gata3-silenced cells. Moreover, Gata3 expression generally paralleled that of Nestin in developing mouse retinas. Both Gata3 and Nestin were expressed in the retina at postnatal day 1 and silenced in the adult mouse retina. Exogenous Gata3 significantly inhibited the neural activity of primary retinal neurocytes (postnatal day 1) by decreasing synaptophysin levels, neurite outgrowth, and cell viability. Furthermore, in vivo, exogenous Gata3 significantly induced apoptosis and the contraction of retinal outlay filaments and decreased the a- and b-waves in adult mouse intravitreal injected with AAV-Re-Gata3-T2A-GFP. Thus, Gata3 silencing promotes neuronal differentiation and neurite outgrowth. Its abnormal expression impedes neural activity in adult retinal neurocytes. This study provides new insights into Gata3 bioactivity in retinal neurocytes.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | | | | | - Keming Yu
- Correspondence: (K.Y.); (J.Z.); Tel.: +86-20-6667-8735 (J.Z.); Fax: +86-20-8733-3271 (J.Z.)
| | - Jing Zhuang
- Correspondence: (K.Y.); (J.Z.); Tel.: +86-20-6667-8735 (J.Z.); Fax: +86-20-8733-3271 (J.Z.)
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22
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mdka Expression Is Associated with Quiescent Neural Stem Cells during Constitutive and Reactive Neurogenesis in the Adult Zebrafish Telencephalon. Brain Sci 2022; 12:brainsci12020284. [PMID: 35204047 PMCID: PMC8870249 DOI: 10.3390/brainsci12020284] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2022] [Revised: 02/09/2022] [Accepted: 02/16/2022] [Indexed: 12/27/2022] Open
Abstract
In contrast to mammals, adult zebrafish display an extraordinary capacity to heal injuries and repair damage in the central nervous system. Pivotal for the regenerative capacity of the zebrafish brain at adult stages is the precise control of neural stem cell (NSC) behavior and the maintenance of the stem cell pool. The gene mdka, a member of a small family of heparin binding growth factors, was previously shown to be involved in regeneration in the zebrafish retina, heart, and fin. Here, we investigated the expression pattern of the gene mdka and its paralogue mdkb in the zebrafish adult telencephalon under constitutive and regenerative conditions. Our findings show that only mdka expression is specifically restricted to the telencephalic ventricle, a stem cell niche of the zebrafish telencephalon. In this brain region, mdka is particularly expressed in the quiescent stem cells. Interestingly, after brain injury, mdka expression remains restricted to the resting stem cell, which might suggest a role of mdka in regulating stem cell quiescence.
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23
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Heller IS, Guenther CA, Meireles AM, Talbot WS, Kingsley DM. Characterization of mouse Bmp5 regulatory injury element in zebrafish wound models. Bone 2022; 155:116263. [PMID: 34826632 PMCID: PMC9007314 DOI: 10.1016/j.bone.2021.116263] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2021] [Revised: 11/17/2021] [Accepted: 11/18/2021] [Indexed: 11/21/2022]
Abstract
Many key signaling molecules used to build tissues during embryonic development are re-activated at injury sites to stimulate tissue regeneration and repair. Bone morphogenetic proteins provide a classic example, but the mechanisms that lead to reactivation of BMPs following injury are still unknown. Previous studies have mapped a large "injury response element" (IRE) in the mouse Bmp5 gene that drives gene expression following bone fractures and other types of injury. Here we show that the large mouse IRE region is also activated in both zebrafish tail resection and mechanosensory hair cell injury models. Using the ability to test multiple constructs and image temporal and spatial dynamics following injury responses, we have narrowed the original size of the mouse IRE region by over 100 fold and identified a small 142 bp minimal enhancer that is rapidly induced in both mesenchymal and epithelial tissues after injury. These studies identify a small sequence that responds to evolutionarily conserved local signals in wounded tissues and suggest candidate pathways that contribute to BMP reactivation after injury.
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Affiliation(s)
- Ian S Heller
- Department of Developmental Biology, Stanford University School of Medicine, United States of America
| | - Catherine A Guenther
- Department of Developmental Biology, Stanford University School of Medicine, United States of America; Howard Hughes Medical Institute, Stanford University School of Medicine, United States of America
| | - Ana M Meireles
- Department of Developmental Biology, Stanford University School of Medicine, United States of America
| | - William S Talbot
- Department of Developmental Biology, Stanford University School of Medicine, United States of America
| | - David M Kingsley
- Department of Developmental Biology, Stanford University School of Medicine, United States of America; Howard Hughes Medical Institute, Stanford University School of Medicine, United States of America.
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24
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Guida N, Mascolo L, Serani A, Cuomo O, Anzilotti S, Brancaccio P, Pignataro G, Molinaro P, Annunziato L, Formisano L. GATA3 (GATA-Binding Protein 3)/KMT2A (Lysine-Methyltransferase-2A) Complex by Increasing H3K4-3me (Trimethylated Lysine-4 of Histone-3) Upregulates NCX3 (Na +-Ca 2+ Exchanger 3) Transcription and Contributes to Ischemic Preconditioning Neuroprotection. Stroke 2021; 52:3680-3691. [PMID: 34694864 DOI: 10.1161/strokeaha.121.034637] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Background and Purpose NCX3 (Na+-Ca2+ exchanger 3) plays a relevant role in stroke; indeed its pharmacological blockade or its genetic ablation exacerbates brain ischemic damage, whereas its upregulation takes part in the neuroprotection elicited by ischemic preconditioning. To identify an effective strategy to induce an overexpression of NCX3, we examined transcription factors and epigenetic mechanisms potentially involved in NCX3 gene regulation. Methods Brain ischemia and ischemic preconditioning were induced in vitro by exposure of cortical neurons to oxygen and glucose deprivation plus reoxygenation (OGD/Reoxy) and in vivo by transient middle cerebral artery occlusion. Western blot and quantitative real-time polymerase chain reaction were used to evaluate transcripts and proteins of GATA3 (GATA-binding protein 3), KMT2A (lysine-methyltransferase-2A), and NCX3. GATA3 and KMT2A binding on NCX3 gene was evaluated by chromatin immunoprecipitation and Rechromatin immunoprecipitation experiments. Results Among the putative transcription factors sharing a consensus sequence on the ncx3 brain promoter region, GATA3 was the only able to up-regulate ncx3. Interestingly, GATA3 physically interacted with KMT2A, and their overexpression or knocking-down increased or downregulated NCX3 mRNA and protein, respectively. Notably, site-direct mutagenesis of GATA site on ncx3 brain promoter region counteracted GATA3 and KMT2A binding on NCX3 gene. More importantly, we found that in the perischemic cortical regions of preconditioned rats GATA3 recruited KMT2A and the complex H3K4-3me (trimethylated lysine-4 of histone-3) on ncx3 brain promoter region, thus reducing transient middle cerebral artery occlusion–induced damage. Consistently, in vivo silencing of either GATA3 or KMT2A prevented NCX3 upregulation and consequently the neuroprotective effect of preconditioning stimulus. The involvement of GATA3/KMT2A complex in neuroprotection elicited by ischemic preconditioning was further confirmed by in vitro experiments in which the knocking-down of GATA3 and KMT2A reverted the neuroprotection induced by NCX3 overexpression in cortical neurons exposed to anoxic preconditioning followed by oxygen and glucose deprivation plus reoxygenation. Conclusions Collectively, our results revealed that GATA3/KMT2A complex epigenetically activates NCX3 gene transcription during ischemic preconditioning.
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Affiliation(s)
| | - Luigi Mascolo
- Division of Pharmacology, Department of Neuroscience, Reproductive and Dentistry Sciences, School of Medicine, "Federico II" University of Naples, Naples, Italy (L.M., O.C., P.B., G.P., P.M., L.F.)
| | - Angelo Serani
- Department of Neuroscience and Brain Technologies, Italian Institute of Technology, Genoa, Italy (A.S.)
| | - Ornella Cuomo
- Division of Pharmacology, Department of Neuroscience, Reproductive and Dentistry Sciences, School of Medicine, "Federico II" University of Naples, Naples, Italy (L.M., O.C., P.B., G.P., P.M., L.F.)
| | | | - Paola Brancaccio
- Division of Pharmacology, Department of Neuroscience, Reproductive and Dentistry Sciences, School of Medicine, "Federico II" University of Naples, Naples, Italy (L.M., O.C., P.B., G.P., P.M., L.F.)
| | - Giuseppe Pignataro
- Division of Pharmacology, Department of Neuroscience, Reproductive and Dentistry Sciences, School of Medicine, "Federico II" University of Naples, Naples, Italy (L.M., O.C., P.B., G.P., P.M., L.F.)
| | - Pasquale Molinaro
- Division of Pharmacology, Department of Neuroscience, Reproductive and Dentistry Sciences, School of Medicine, "Federico II" University of Naples, Naples, Italy (L.M., O.C., P.B., G.P., P.M., L.F.)
| | | | - Luigi Formisano
- Division of Pharmacology, Department of Neuroscience, Reproductive and Dentistry Sciences, School of Medicine, "Federico II" University of Naples, Naples, Italy (L.M., O.C., P.B., G.P., P.M., L.F.)
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25
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Zhang G, Lübke L, Chen F, Beil T, Takamiya M, Diotel N, Strähle U, Rastegar S. Neuron-Radial Glial Cell Communication via BMP/Id1 Signaling Is Key to Long-Term Maintenance of the Regenerative Capacity of the Adult Zebrafish Telencephalon. Cells 2021; 10:cells10102794. [PMID: 34685774 PMCID: PMC8534405 DOI: 10.3390/cells10102794] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2021] [Revised: 10/12/2021] [Accepted: 10/15/2021] [Indexed: 01/17/2023] Open
Abstract
The central nervous system of adult zebrafish displays an extraordinary neurogenic and regenerative capacity. In the zebrafish adult brain, this regenerative capacity relies on neural stem cells (NSCs) and the careful management of the NSC pool. However, the mechanisms controlling NSC pool maintenance are not yet fully understood. Recently, Bone Morphogenetic Proteins (BMPs) and their downstream effector Id1 (Inhibitor of differentiation 1) were suggested to act as key players in NSC maintenance under constitutive and regenerative conditions. Here, we further investigated the role of BMP/Id1 signaling in these processes, using different genetic and pharmacological approaches. Our data show that BMPs are mainly expressed by neurons in the adult telencephalon, while id1 is expressed in NSCs, suggesting a neuron-NSC communication via the BMP/Id1 signaling axis. Furthermore, manipulation of BMP signaling by conditionally inducing or repressing BMP signaling via heat-shock, lead to an increase or a decrease of id1 expression in the NSCs, respectively. Induction of id1 was followed by an increase in the number of quiescent NSCs, while knocking down id1 expression caused an increase in NSC proliferation. In agreement, genetic ablation of id1 function lead to increased proliferation of NSCs, followed by depletion of the stem cell pool with concomitant failure to heal injuries in repeatedly injured mutant telencephala. Moreover, pharmacological inhibition of BMP and Notch signaling suggests that the two signaling systems cooperate and converge onto the transcriptional regulator her4.1. Interestingly, brain injury lead to a depletion of NSCs in animals lacking BMP/Id1 signaling despite an intact Notch pathway. Taken together, our data demonstrate how neurons feedback on NSC proliferation and that BMP1/Id1 signaling acts as a safeguard of the NSC pool under regenerative conditions.
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Affiliation(s)
- Gaoqun Zhang
- Institute of Biological and Chemical Systems-Biological Information Processing (IBCS-BIP), Karlsruhe Institute of Technology (KIT), Postfach 3640, 76021 Karlsruhe, Germany; (G.Z.); (L.L.); (F.C.); (T.B.); (M.T.)
| | - Luisa Lübke
- Institute of Biological and Chemical Systems-Biological Information Processing (IBCS-BIP), Karlsruhe Institute of Technology (KIT), Postfach 3640, 76021 Karlsruhe, Germany; (G.Z.); (L.L.); (F.C.); (T.B.); (M.T.)
| | - Fushun Chen
- Institute of Biological and Chemical Systems-Biological Information Processing (IBCS-BIP), Karlsruhe Institute of Technology (KIT), Postfach 3640, 76021 Karlsruhe, Germany; (G.Z.); (L.L.); (F.C.); (T.B.); (M.T.)
| | - Tanja Beil
- Institute of Biological and Chemical Systems-Biological Information Processing (IBCS-BIP), Karlsruhe Institute of Technology (KIT), Postfach 3640, 76021 Karlsruhe, Germany; (G.Z.); (L.L.); (F.C.); (T.B.); (M.T.)
| | - Masanari Takamiya
- Institute of Biological and Chemical Systems-Biological Information Processing (IBCS-BIP), Karlsruhe Institute of Technology (KIT), Postfach 3640, 76021 Karlsruhe, Germany; (G.Z.); (L.L.); (F.C.); (T.B.); (M.T.)
| | - Nicolas Diotel
- Diabète Athérothrombose Thérapies Réunion Océan Indien, INSERM, UMR 1188, Université de La Réunion, 97400 Saint-Denis de La Réunion, France;
| | - Uwe Strähle
- Institute of Biological and Chemical Systems-Biological Information Processing (IBCS-BIP), Karlsruhe Institute of Technology (KIT), Postfach 3640, 76021 Karlsruhe, Germany; (G.Z.); (L.L.); (F.C.); (T.B.); (M.T.)
- Centre of Organismal Studies, University Heidelberg, Im Neuenheimer Feld 230, 69120 Heidelberg, Germany
- Correspondence: (U.S.); (S.R.)
| | - Sepand Rastegar
- Institute of Biological and Chemical Systems-Biological Information Processing (IBCS-BIP), Karlsruhe Institute of Technology (KIT), Postfach 3640, 76021 Karlsruhe, Germany; (G.Z.); (L.L.); (F.C.); (T.B.); (M.T.)
- Correspondence: (U.S.); (S.R.)
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26
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Siddiqui T, Bhattarai P, Popova S, Cosacak MI, Sariya S, Zhang Y, Mayeux R, Tosto G, Kizil C. KYNA/Ahr Signaling Suppresses Neural Stem Cell Plasticity and Neurogenesis in Adult Zebrafish Model of Alzheimer's Disease. Cells 2021; 10:2748. [PMID: 34685728 PMCID: PMC8534484 DOI: 10.3390/cells10102748] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2021] [Revised: 10/05/2021] [Accepted: 10/08/2021] [Indexed: 12/13/2022] Open
Abstract
Neurogenesis decreases in Alzheimer's disease (AD) patients, suggesting that restoring the normal neurogenic response could be a disease modifying intervention. To study the mechanisms of pathology-induced neuro-regeneration in vertebrate brains, zebrafish is an excellent model due to its extensive neural regeneration capacity. Here, we report that Kynurenic acid (KYNA), a metabolite of the amino acid tryptophan, negatively regulates neural stem cell (NSC) plasticity in adult zebrafish brain through its receptor, aryl hydrocarbon receptor 2 (Ahr2). The production of KYNA is suppressed after amyloid-toxicity through reduction of the levels of Kynurenine amino transferase 2 (KAT2), the key enzyme producing KYNA. NSC proliferation is enhanced by an antagonist for Ahr2 and is reduced with Ahr2 agonists or KYNA. A subset of Ahr2-expressing zebrafish NSCs do not express other regulatory receptors such as il4r or ngfra, indicating that ahr2-positive NSCs constitute a new subset of neural progenitors that are responsive to amyloid-toxicity. By performing transcriptome-wide association studies (TWAS) in three late onset Alzheimer disease (LOAD) brain autopsy cohorts, we also found that several genes that are components of KYNA metabolism or AHR signaling are differentially expressed in LOAD, suggesting a strong link between KYNA/Ahr2 signaling axis to neurogenesis in LOAD.
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Affiliation(s)
- Tohid Siddiqui
- German Center for Neurodegenerative Diseases (DZNE) within Helmholtz Association, Tatzberg 41, 01307 Dresden, Germany; (T.S.); (P.B.); (S.P.); (M.I.C.)
| | - Prabesh Bhattarai
- German Center for Neurodegenerative Diseases (DZNE) within Helmholtz Association, Tatzberg 41, 01307 Dresden, Germany; (T.S.); (P.B.); (S.P.); (M.I.C.)
| | - Stanislava Popova
- German Center for Neurodegenerative Diseases (DZNE) within Helmholtz Association, Tatzberg 41, 01307 Dresden, Germany; (T.S.); (P.B.); (S.P.); (M.I.C.)
| | - Mehmet Ilyas Cosacak
- German Center for Neurodegenerative Diseases (DZNE) within Helmholtz Association, Tatzberg 41, 01307 Dresden, Germany; (T.S.); (P.B.); (S.P.); (M.I.C.)
| | - Sanjeev Sariya
- The Department of Neurology, The Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Columbia University Irving Medical Center, 630 West 168th Street, New York, NY 10032, USA; (S.S.); (R.M.); (G.T.)
| | - Yixin Zhang
- B-CUBE, Center for Molecular Bioengineering, TU Dresden, Tatzberg 41, 01307 Dresden, Germany;
| | - Richard Mayeux
- The Department of Neurology, The Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Columbia University Irving Medical Center, 630 West 168th Street, New York, NY 10032, USA; (S.S.); (R.M.); (G.T.)
| | - Giuseppe Tosto
- The Department of Neurology, The Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Columbia University Irving Medical Center, 630 West 168th Street, New York, NY 10032, USA; (S.S.); (R.M.); (G.T.)
| | - Caghan Kizil
- German Center for Neurodegenerative Diseases (DZNE) within Helmholtz Association, Tatzberg 41, 01307 Dresden, Germany; (T.S.); (P.B.); (S.P.); (M.I.C.)
- The Department of Neurology, The Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Columbia University Irving Medical Center, 630 West 168th Street, New York, NY 10032, USA; (S.S.); (R.M.); (G.T.)
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27
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Locomotion dependent neuron-glia interactions control neurogenesis and regeneration in the adult zebrafish spinal cord. Nat Commun 2021; 12:4857. [PMID: 34381039 PMCID: PMC8357999 DOI: 10.1038/s41467-021-25052-1] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Accepted: 07/21/2021] [Indexed: 01/09/2023] Open
Abstract
Physical exercise stimulates adult neurogenesis, yet the underlying mechanisms remain poorly understood. A fundamental component of the innate neuroregenerative capacity of zebrafish is the proliferative and neurogenic ability of the neural stem/progenitor cells. Here, we show that in the intact spinal cord, this plasticity response can be activated by physical exercise by demonstrating that the cholinergic neurotransmission from spinal locomotor neurons activates spinal neural stem/progenitor cells, leading to neurogenesis in the adult zebrafish. We also show that GABA acts in a non-synaptic fashion to maintain neural stem/progenitor cell quiescence in the spinal cord and that training-induced activation of neurogenesis requires a reduction of GABAA receptors. Furthermore, both pharmacological stimulation of cholinergic receptors, as well as interference with GABAergic signaling, promote functional recovery after spinal cord injury. Our findings provide a model for locomotor networks’ activity-dependent neurogenesis during homeostasis and regeneration in the adult zebrafish spinal cord. The mechanisms stimulating adult neurogenesis are unclear. Here, the authors show the contribution of cholinergic and GABAergic signalling within the locomotor network to spinal cord neurogenesis during homeostasis and regeneration, showing neurogenesis depends on circuit activity in the adult zebrafish.
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Shimizu Y, Kawasaki T. Histone acetyltransferase EP300 regulates the proliferation and differentiation of neural stem cells during adult neurogenesis and regenerative neurogenesis in the zebrafish optic tectum. Neurosci Lett 2021; 756:135978. [PMID: 34023416 DOI: 10.1016/j.neulet.2021.135978] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Revised: 03/07/2021] [Accepted: 05/19/2021] [Indexed: 10/21/2022]
Abstract
Zebrafish have a greater capacity for adult neurogenesis and brain regeneration than mammals. In the adult zebrafish optic tectum (OT), neuroepithelial-like stem cells (NE) contribute to adult neurogenesis, whereas radial glia (RG) contribute to neuronal regeneration after the stab wound injury. The molecular mechanisms regulated by acetylated histone play important roles in these events; however, the functions of histone acetyltransferase (HAT) require further elucidation. The aim of this study was to study the proliferation and differentiation of neural stem cells (NSCs) following treatment with C646, a HAT EP300 inhibitor, to identify the functions of HAT in adult neurogenesis and neuronal regeneration. C646 treatment decreased acetylation of histone 3 lysine 9 in the adult OT. Under physiological conditions, C646 promoted NE proliferation and generation of newborn neurons. EP300 inhibition promoted RG proliferation but suppressed the generation of newborn neurons after the injury. EP300 inhibition downregulated the Notch target genes her4 and her6, which was correlated with NE and RG proliferation in the adult OT. EP300 inhibition regulates the proliferation and differentiation of NSCs by inhibiting histone acetylation and Notch target genes expression, suggesting that the functions of HAT in neurogenesis are opposite to those of histone deacetylase.
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Affiliation(s)
- Yuki Shimizu
- Functional Biomolecular Research Group and Biomedical Research Institute, AIST, 1-8-31, Midorigaoka, Ikeda, Osaka, 563-8577, Japan; DBT-AIST International Laboratory for Advanced Biomedicine (DAILAB), AIST, 1-8-31, Midorigaoka, Ikeda, Osaka, 563-8577, Japan.
| | - Takashi Kawasaki
- Functional Biomolecular Research Group and Biomedical Research Institute, AIST, 1-8-31, Midorigaoka, Ikeda, Osaka, 563-8577, Japan
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29
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Gourain V, Armant O, Lübke L, Diotel N, Rastegar S, Strähle U. Multi-Dimensional Transcriptome Analysis Reveals Modulation of Cholesterol Metabolism as Highly Integrated Response to Brain Injury. Front Neurosci 2021; 15:671249. [PMID: 34054419 PMCID: PMC8162057 DOI: 10.3389/fnins.2021.671249] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Accepted: 04/16/2021] [Indexed: 12/14/2022] Open
Abstract
Zebrafish is an attractive model to investigate regeneration of the nervous system. Despite major progress in our understanding of the underlying processes, the transcriptomic changes are largely unknown. We carried out a computational analysis of the transcriptome of the regenerating telencephalon integrating changes in the expression of mRNAs, their splice variants and investigated the putative role of regulatory RNAs in the modulation of these transcriptional changes. Profound changes in the expression of genes and their splice variants engaged in many distinct processes were observed. Differential transcription and splicing are important processes in response to injury of the telencephalon. As exemplified by the coordinated regulation of the cholesterol synthesizing enzymes and transporters, the genome responded to injury of the telencephalon in a multi-tiered manner with distinct and interwoven changes in expression of enzymes, transporters and their regulatory molecules. This coordinated genomic response involved a decrease of the mRNA of the key transcription factor SREBF2, induction of microRNAs (miR-182, miR-155, miR-146, miR-31) targeting cholesterol genes, shifts in abundance of splice variants as well as regulation of long non-coding RNAs. Cholesterol metabolism appears to be switched from synthesis to relocation of cholesterol. Based on our in silico analyses, this switch involves complementary and synergistic inputs by different regulatory principles. Our studies suggest that adaptation of cholesterol metabolism is a key process involved in regeneration of the injured zebrafish brain.
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Affiliation(s)
- Victor Gourain
- Institute of Biological and Chemical Systems-Biological Information Processing (IBCS-BIP), Karlsruhe Institute of Technology (KIT), Karlsruhe, Germany.,UMR 1064 Centre de Recherche en Transplantation en Immunologie, Nantes, France
| | - Olivier Armant
- Institute of Biological and Chemical Systems-Biological Information Processing (IBCS-BIP), Karlsruhe Institute of Technology (KIT), Karlsruhe, Germany.,PSE-ENV/SRTE/LECO, Institut de Radioprotection et de Sûreté Nucléaire (IRSN), Cadarache, Saint-Paul-Lez-Durance, France
| | - Luisa Lübke
- Institute of Biological and Chemical Systems-Biological Information Processing (IBCS-BIP), Karlsruhe Institute of Technology (KIT), Karlsruhe, Germany
| | - Nicolas Diotel
- Institute of Biological and Chemical Systems-Biological Information Processing (IBCS-BIP), Karlsruhe Institute of Technology (KIT), Karlsruhe, Germany.,UMR 1188, Diabète Athérothrombose Thérapies Réunion Océan Indien CYROI, Saint-Denis, France
| | - Sepand Rastegar
- Institute of Biological and Chemical Systems-Biological Information Processing (IBCS-BIP), Karlsruhe Institute of Technology (KIT), Karlsruhe, Germany
| | - Uwe Strähle
- Institute of Biological and Chemical Systems-Biological Information Processing (IBCS-BIP), Karlsruhe Institute of Technology (KIT), Karlsruhe, Germany.,COS, University Heidelberg, Heidelberg, Germany
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30
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Zulazmi NA, Arulsamy A, Ali I, Zainal Abidin SA, Othman I, Shaikh MF. The utilization of small non-mammals in traumatic brain injury research: A systematic review. CNS Neurosci Ther 2021; 27:381-402. [PMID: 33539662 PMCID: PMC7941175 DOI: 10.1111/cns.13590] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2020] [Revised: 12/07/2020] [Accepted: 12/14/2020] [Indexed: 12/20/2022] Open
Abstract
Traumatic brain injury (TBI) is the leading cause of death and disability worldwide and has complicated underlying pathophysiology. Numerous TBI animal models have been developed over the past decade to effectively mimic the human TBI pathophysiology. These models are of mostly mammalian origin including rodents and non-human primates. However, the mammalian models demanded higher costs and have lower throughput often limiting the progress in TBI research. Thus, this systematic review aims to discuss the potential benefits of non-mammalian TBI models in terms of their face validity in resembling human TBI. Three databases were searched as follows: PubMed, Scopus, and Embase, for original articles relating to non-mammalian TBI models, published between January 2010 and December 2019. A total of 29 articles were selected based on PRISMA model for critical appraisal. Zebrafish, both larvae and adult, was found to be the most utilized non-mammalian TBI model in the current literature, followed by the fruit fly and roundworm. In conclusion, non-mammalian TBI models have advantages over mammalian models especially for rapid, cost-effective, and reproducible screening of effective treatment strategies and provide an opportunity to expedite the advancement of TBI research.
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Affiliation(s)
- Nurul Atiqah Zulazmi
- Neuropharmacology Research LaboratoryJeffrey Cheah School of Medicine and Health SciencesMonash University MalaysiaSelangor Darul EhsanMalaysia
| | - Alina Arulsamy
- Neuropharmacology Research LaboratoryJeffrey Cheah School of Medicine and Health SciencesMonash University MalaysiaSelangor Darul EhsanMalaysia
| | - Idrish Ali
- Department of NeuroscienceCentral Clinical SchoolThe Alfred HospitalMonash UniversityMelbourneVic.Australia
| | - Syafiq Asnawi Zainal Abidin
- Neuropharmacology Research LaboratoryJeffrey Cheah School of Medicine and Health SciencesMonash University MalaysiaSelangor Darul EhsanMalaysia
- Liquid Chromatography Mass Spectrometry (LCMS) PlatformJeffrey Cheah School of Medicine and Health SciencesMonash University MalaysiaSelangor Darul EhsanMalaysia
| | - Iekhsan Othman
- Neuropharmacology Research LaboratoryJeffrey Cheah School of Medicine and Health SciencesMonash University MalaysiaSelangor Darul EhsanMalaysia
- Liquid Chromatography Mass Spectrometry (LCMS) PlatformJeffrey Cheah School of Medicine and Health SciencesMonash University MalaysiaSelangor Darul EhsanMalaysia
| | - Mohd. Farooq Shaikh
- Neuropharmacology Research LaboratoryJeffrey Cheah School of Medicine and Health SciencesMonash University MalaysiaSelangor Darul EhsanMalaysia
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31
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Cellular Mechanisms Participating in Brain Repair of Adult Zebrafish and Mammals after Injury. Cells 2021; 10:cells10020391. [PMID: 33672842 PMCID: PMC7917790 DOI: 10.3390/cells10020391] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Revised: 01/28/2021] [Accepted: 02/05/2021] [Indexed: 12/12/2022] Open
Abstract
Adult neurogenesis is an evolutionary conserved process occurring in all vertebrates. However, striking differences are observed between the taxa, considering the number of neurogenic niches, the neural stem cell (NSC) identity, and brain plasticity under constitutive and injury-induced conditions. Zebrafish has become a popular model for the investigation of the molecular and cellular mechanisms involved in adult neurogenesis. Compared to mammals, the adult zebrafish displays a high number of neurogenic niches distributed throughout the brain. Furthermore, it exhibits a strong regenerative capacity without scar formation or any obvious disabilities. In this review, we will first discuss the similarities and differences regarding (i) the distribution of neurogenic niches in the brain of adult zebrafish and mammals (mainly mouse) and (ii) the nature of the neural stem cells within the main telencephalic niches. In the second part, we will describe the cascade of cellular events occurring after telencephalic injury in zebrafish and mouse. Our study clearly shows that most early events happening right after the brain injury are shared between zebrafish and mouse including cell death, microglia, and oligodendrocyte recruitment, as well as injury-induced neurogenesis. In mammals, one of the consequences following an injury is the formation of a glial scar that is persistent. This is not the case in zebrafish, which may be one of the main reasons that zebrafish display a higher regenerative capacity.
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Mechanical Brain Injury Increases Cells' Production of Cystathionine β-Synthase and Glutamine Synthetase, but Reduces Pax2 Expression in the Telencephalon of Juvenile Chum Salmon, Oncorhynchus keta. Int J Mol Sci 2021; 22:ijms22031279. [PMID: 33525421 PMCID: PMC7865298 DOI: 10.3390/ijms22031279] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2020] [Revised: 01/15/2021] [Accepted: 01/20/2021] [Indexed: 12/15/2022] Open
Abstract
The considerable post-traumatic brain recovery in fishes makes them a useful model for studying the mechanisms that provide reparative neurogenesis, which is poorly represented in mammals. After a mechanical injury to the telencephalon in adult fish, lost neurons are actively replaced due to the proliferative activity of neuroepithelial cells and radial glia in the neurogenic periventricular zone. However, it is not enough clear which signaling mechanisms are involved in the activation of adult neural stem cells (aNSC) after the injury (reactive proliferation) and in the production of new neurons (regenerative neurogenesis) from progenitor cells (NPC). In juvenile Pacific salmon, the predominant type of NSCs in the telencephalon are neuroepithelial cells corresponding to embryonic NSCs. Expression of glutamine synthetase (GS), a NSC molecular marker, was detected in the neuroepithelial cells of the pallium and subpallium of juvenile chum salmon, Oncorhynchus keta. At 3 days after a traumatic brain injury (TBI) in juvenile chum salmon, the GS expression was detected in the radial glia corresponding to aNSC in the pallium and subpallium. The maximum density of distribution of GS+ radial glia was found in the dorsal pallial region. Hydrogen sulfide (H2S) is a proneurogenic factor that reduces oxidative stress and excitotoxicity effects, along with the increased GS production in the brain cells of juvenile chum salmon. In the fish brain, H2S producing by cystathionine β-synthase in neurogenic zones may be involved in maintaining the microenvironment that provides optimal conditions for the functioning of neurogenic niches during constitutive neurogenesis. After injury, H2S can determine cell survivability, providing a neuroprotective effect in the area of injury and reducing the process of glutamate excitotoxicity, acting as a signaling molecule involved in changing the neurogenic environment, which leads to the reactivation of neurogenic niches and cell regeneration programs. The results of studies on the control of the expression of regulatory Sonic Hedgehog genes (Shh) and the transcription factors Paired Box2 (Pax2) regulated by them are still insufficient. A comparative analysis of Pax2 expression in the telencephalon of intact chum salmon showed the presence of constitutive patterns of Pax2 expression in neurogenic areas and non-neurogenic parenchymal zones of the pallium and subpallium. After mechanical injury, the patterns of Pax2 expression changed, and the amount of Pax2+ decreased (p < 0.05) in lateral (Dl), medial (Dm) zones of the pallium, and the lateral zone (Vl) of the subpallium compared to the control. We believe that the decrease in the expression of Pax2 may be caused by the inhibitory effect of the Pax6 transcription factor, whose expression in the juvenile salmon brain increases upon injury.
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33
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Massoz L, Dupont MA, Manfroid I. Zebra-Fishing for Regenerative Awakening in Mammals. Biomedicines 2021; 9:65. [PMID: 33445518 PMCID: PMC7827770 DOI: 10.3390/biomedicines9010065] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Revised: 01/04/2021] [Accepted: 01/05/2021] [Indexed: 02/07/2023] Open
Abstract
Regeneration is defined as the ability to regrow an organ or a tissue destroyed by degeneration or injury. Many human degenerative diseases and pathologies, currently incurable, could be cured if functional tissues or cells could be restored. Unfortunately, humans and more generally mammals have limited regenerative capabilities, capacities that are even further declining with age, contrary to simpler organisms. Initially thought to be lost during evolution, several studies have revealed that regenerative mechanisms are still present in mammals but are latent and thus they could be stimulated. To do so there is a pressing need to identify the fundamental mechanisms of regeneration in species able to efficiently regenerate. Thanks to its ability to regenerate most of its organs and tissues, the zebrafish has become a powerful model organism in regenerative biology and has recently engendered a number of studies attesting the validity of awakening the regenerative potential in mammals. In this review we highlight studies, particularly in the liver, pancreas, retina, heart, brain and spinal cord, which have identified conserved regenerative molecular events that proved to be beneficial to restore murine and even human cells and which helped clarify the real clinical translation potential of zebrafish research to mammals.
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Affiliation(s)
| | | | - Isabelle Manfroid
- Zebrafish Development and Disease Models Laboratory, GIGA-Stem Cells, University of Liège, B-4000 Liège, Belgium; (L.M.); (M.A.D.)
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34
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Jia Y, Wang G, Ye Y, Kang E, Chen H, Guo Z, He X. Niche Cells Crosstalk In Neuroinflammation After Traumatic Brain Injury. Int J Biol Sci 2021; 17:368-378. [PMID: 33390856 PMCID: PMC7757042 DOI: 10.7150/ijbs.52169] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2020] [Accepted: 11/23/2020] [Indexed: 12/12/2022] Open
Abstract
Traumatic brain injury (TBI) is recognized as the disease with high morbidity and disability around world in spite of the work ongoing in neural protection. Due to heterogeneity among the patients, it's still hard to acquire satisfying achievements in clinic. Neuroinflammation, which exists since primary injury occurs, with elusive duality, appear to be of significance from recovery of injury to neurogenesis. In recent years, studied have revealed that communication in neurogenic niche is more than “cell to cell” communication, and study on NSCs represent it as central role in the progress of neural regeneration. Hence, the neuroinflammation-affecting crosstalk after TBI, and clarifying definitive role of NSCs in the course of regeneration is a promising subject for researchers, for its great potential in overcoming the frustrating status quo in clinic, promoting welfare of TBI patient.
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Affiliation(s)
- Yibin Jia
- Department of Neurosurgery, Xijing Hospital, Airforce Military Medical University (Fourth Military Medical University), Xi'an 710032, China
| | - Guanyi Wang
- Department of Neurosurgery, Xijing Hospital, Airforce Military Medical University (Fourth Military Medical University), Xi'an 710032, China
| | - Yuqing Ye
- Department of Neurosurgery, Xijing Hospital, Airforce Military Medical University (Fourth Military Medical University), Xi'an 710032, China.,Department of Neurosurgery, PLA 163rd Hospital (Second Affiliated Hospital of Hunan Normal University), Changsha 410000, China
| | - Enming Kang
- Department of Neurosurgery, Xijing Hospital, Airforce Military Medical University (Fourth Military Medical University), Xi'an 710032, China
| | - Huijun Chen
- Department of Neurosurgery, Xijing Hospital, Airforce Military Medical University (Fourth Military Medical University), Xi'an 710032, China
| | - Zishuo Guo
- State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, AMMS, Beijing 100071, China
| | - Xiaosheng He
- Department of Neurosurgery, Xijing Hospital, Airforce Military Medical University (Fourth Military Medical University), Xi'an 710032, China
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35
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Demirci Y, Cucun G, Poyraz YK, Mohammed S, Heger G, Papatheodorou I, Ozhan G. Comparative Transcriptome Analysis of the Regenerating Zebrafish Telencephalon Unravels a Resource With Key Pathways During Two Early Stages and Activation of Wnt/β-Catenin Signaling at the Early Wound Healing Stage. Front Cell Dev Biol 2020; 8:584604. [PMID: 33163496 PMCID: PMC7581945 DOI: 10.3389/fcell.2020.584604] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2020] [Accepted: 09/11/2020] [Indexed: 01/22/2023] Open
Abstract
Owing to its pronounced regenerative capacity in many tissues and organs, the zebrafish brain represents an ideal platform to understand the endogenous regeneration mechanisms that restore tissue integrity and function upon injury or disease. Although radial glial and neuronal cell populations have been characterized with respect to specific marker genes, comprehensive transcriptomic profiling of the regenerating telencephalon has not been conducted so far. Here, by processing the lesioned and unlesioned hemispheres of the telencephalon separately, we reveal the differentially expressed genes (DEGs) at the early wound healing and early proliferative stages of regeneration, i.e., 20 h post-lesion (hpl) and 3 days post-lesion (dpl), respectively. At 20 hpl, we detect a far higher number of DEGs in the lesioned hemisphere than in the unlesioned half and only 7% of all DEGs in both halves. However, this difference disappears at 3 dpl, where the lesioned and unlesioned hemispheres share 40% of all DEGs. By performing an extensive comparison of the gene expression profiles in these stages, we unravel that the lesioned hemispheres at 20 hpl and 3 dpl exhibit distinct transcriptional profiles. We further unveil a prominent activation of Wnt/β-catenin signaling at 20 hpl, returning to control level in the lesioned site at 3 dpl. Wnt/β-catenin signaling indeed appears to control a large number of genes associated primarily with the p53, apoptosis, forkhead box O (FoxO), mitogen-activated protein kinase (MAPK), and mammalian target of rapamycin (mTOR) signaling pathways specifically at 20 hpl. Based on these results, we propose that the lesioned and unlesioned hemispheres react to injury dynamically during telencephalon regeneration and that the activation of Wnt/β-catenin signaling at the early wound healing stage plays a key role in the regulation of cellular and molecular events.
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Affiliation(s)
- Yeliz Demirci
- İzmir Biomedicine and Genome Center (IBG), Dokuz Eylül University Health Campus, İzmir, Turkey.,İzmir International Biomedicine and Genome Institute (IBG-İzmir), Dokuz Eylül University, İzmir, Turkey.,European Molecular Biology Laboratory - European Bioinformatics Institute (EMBL-EBI), Cambridge, United Kingdom
| | - Gokhan Cucun
- İzmir Biomedicine and Genome Center (IBG), Dokuz Eylül University Health Campus, İzmir, Turkey.,İzmir International Biomedicine and Genome Institute (IBG-İzmir), Dokuz Eylül University, İzmir, Turkey
| | - Yusuf Kaan Poyraz
- İzmir Biomedicine and Genome Center (IBG), Dokuz Eylül University Health Campus, İzmir, Turkey.,İzmir International Biomedicine and Genome Institute (IBG-İzmir), Dokuz Eylül University, İzmir, Turkey
| | - Suhaib Mohammed
- European Molecular Biology Laboratory - European Bioinformatics Institute (EMBL-EBI), Cambridge, United Kingdom
| | | | - Irene Papatheodorou
- European Molecular Biology Laboratory - European Bioinformatics Institute (EMBL-EBI), Cambridge, United Kingdom
| | - Gunes Ozhan
- İzmir Biomedicine and Genome Center (IBG), Dokuz Eylül University Health Campus, İzmir, Turkey.,İzmir International Biomedicine and Genome Institute (IBG-İzmir), Dokuz Eylül University, İzmir, Turkey
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36
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Wu CC, Brugeaud A, Seist R, Lin HC, Yeh WH, Petrillo M, Coppola G, Edge ASB, Stankovic KM. Altered expression of genes regulating inflammation and synaptogenesis during regrowth of afferent neurons to cochlear hair cells. PLoS One 2020; 15:e0238578. [PMID: 33001981 PMCID: PMC7529247 DOI: 10.1371/journal.pone.0238578] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2020] [Accepted: 08/19/2020] [Indexed: 12/20/2022] Open
Abstract
The spiral ganglion neurons constitute the primary connection between auditory hair cells and the brain. The spiral ganglion afferent fibers and their synapse with hair cells do not regenerate to any significant degree in adult mammalian ears after damage. We have investigated gene expression changes after kainate-induced disruption of the synapses in a neonatal cochlear explant model in which peripheral fibers and the afferent synapse do regenerate. We compared gene expression early after damage, during regeneration of the fibers and synapses, and after completion of in vitro regeneration. These analyses revealed a total of 2.5% differentially regulated transcripts (588 out of 24,000) based on a threshold of p<0.005. Inflammatory response genes as well as genes involved in regeneration of neural circuits were upregulated in the spiral ganglion neurons and organ of Corti, where the hair cells reside. Prominent genes upregulated at several time points included genes with roles in neurogenesis (Elavl4 and Sox21), neural outgrowth (Ntrk3 and Ppp1r1c), axonal guidance (Rgmb and Sema7a), synaptogenesis (Nlgn2 and Psd2), and synaptic vesicular function (Syt8 and Syn1). Immunohistochemical and in situ hybridization analysis of genes that had not previously been described in the cochlea confirmed their cochlear expression. The time course of expression of these genes suggests that kainate treatment resulted in a two-phase response in spiral ganglion neurons: an acute response consistent with inflammation, followed by an upregulation of neural regeneration genes. Identification of the genes activated during regeneration of these fibers suggests candidates that could be targeted to enhance regeneration in adult ears.
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Affiliation(s)
- Chen-Chi Wu
- Eaton Peabody Laboratories and Department of Otolaryngology—Head and Neck Surgery, Massachusetts Eye and Ear, Boston, Massachusetts, United States of America
- Department of Otolaryngology—Head and Neck Surgery, Harvard Medical School, Boston, Massachusetts, United States of America
| | - Aurore Brugeaud
- Eaton Peabody Laboratories and Department of Otolaryngology—Head and Neck Surgery, Massachusetts Eye and Ear, Boston, Massachusetts, United States of America
- Department of Otolaryngology—Head and Neck Surgery, Harvard Medical School, Boston, Massachusetts, United States of America
| | - Richard Seist
- Eaton Peabody Laboratories and Department of Otolaryngology—Head and Neck Surgery, Massachusetts Eye and Ear, Boston, Massachusetts, United States of America
- Department of Otolaryngology—Head and Neck Surgery, Harvard Medical School, Boston, Massachusetts, United States of America
- Department of Otorhinolaryngology-Head and Neck Surgery, Paracelsus Medical University, Salzburg, Austria
| | - Hsiao-Chun Lin
- Eaton Peabody Laboratories and Department of Otolaryngology—Head and Neck Surgery, Massachusetts Eye and Ear, Boston, Massachusetts, United States of America
- Department of Otolaryngology—Head and Neck Surgery, Harvard Medical School, Boston, Massachusetts, United States of America
| | - Wei-Hsi Yeh
- Eaton Peabody Laboratories and Department of Otolaryngology—Head and Neck Surgery, Massachusetts Eye and Ear, Boston, Massachusetts, United States of America
- Department of Otolaryngology—Head and Neck Surgery, Harvard Medical School, Boston, Massachusetts, United States of America
- Program in Speech and Hearing Bioscience and Technology, Harvard Medical School, Boston, Massachusetts, United States of America
| | - Marco Petrillo
- Eaton Peabody Laboratories and Department of Otolaryngology—Head and Neck Surgery, Massachusetts Eye and Ear, Boston, Massachusetts, United States of America
- Department of Otolaryngology—Head and Neck Surgery, Harvard Medical School, Boston, Massachusetts, United States of America
| | - Giovanni Coppola
- Program in Neurogenetics, Department of Neurology, University of California Los Angeles, Los Angeles, California, United States of America
| | - Albert S. B. Edge
- Eaton Peabody Laboratories and Department of Otolaryngology—Head and Neck Surgery, Massachusetts Eye and Ear, Boston, Massachusetts, United States of America
- Department of Otolaryngology—Head and Neck Surgery, Harvard Medical School, Boston, Massachusetts, United States of America
- Program in Speech and Hearing Bioscience and Technology, Harvard Medical School, Boston, Massachusetts, United States of America
| | - Konstantina M. Stankovic
- Eaton Peabody Laboratories and Department of Otolaryngology—Head and Neck Surgery, Massachusetts Eye and Ear, Boston, Massachusetts, United States of America
- Department of Otolaryngology—Head and Neck Surgery, Harvard Medical School, Boston, Massachusetts, United States of America
- Program in Speech and Hearing Bioscience and Technology, Harvard Medical School, Boston, Massachusetts, United States of America
- Harvard Program in Therapeutic Science, Harvard Medical School, Boston, Massachusetts, United States of America
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37
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Diotel N, Lübke L, Strähle U, Rastegar S. Common and Distinct Features of Adult Neurogenesis and Regeneration in the Telencephalon of Zebrafish and Mammals. Front Neurosci 2020; 14:568930. [PMID: 33071740 PMCID: PMC7538694 DOI: 10.3389/fnins.2020.568930] [Citation(s) in RCA: 52] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Accepted: 08/19/2020] [Indexed: 12/11/2022] Open
Abstract
In contrast to mammals, the adult zebrafish brain shows neurogenic activity in a multitude of niches present in almost all brain subdivisions. Irrespectively, constitutive neurogenesis in the adult zebrafish and mouse telencephalon share many similarities at the cellular and molecular level. However, upon injury during tissue repair, the situation is entirely different. In zebrafish, inflammation caused by traumatic brain injury or by induced neurodegeneration initiates specific and distinct neurogenic programs that, in combination with signaling pathways implicated in constitutive neurogenesis, quickly, and efficiently overcome the loss of neurons. In the mouse brain, injury-induced inflammation promotes gliosis leading to glial scar formation and inhibition of regeneration. A better understanding of the regenerative mechanisms occurring in the zebrafish brain could help to develop new therapies to combat the debilitating consequences of brain injury, stroke, and neurodegeneration. The aim of this review is to compare the properties of neural progenitors and the signaling pathways, which control adult neurogenesis and regeneration in the zebrafish and mammalian telencephalon.
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Affiliation(s)
- Nicolas Diotel
- INSERM, UMR 1188, Diabète athérothrombose Thérapies Réunion Océan Indien (DéTROI), Université de La Réunion, Saint-Denis, France
| | - Luisa Lübke
- Institute of Biological and Chemical Systems-Biological Information Processing (IBCS-BIP), Karlsruhe Institute of Technology (KIT), Karlsruhe, Germany
| | - Uwe Strähle
- Institute of Biological and Chemical Systems-Biological Information Processing (IBCS-BIP), Karlsruhe Institute of Technology (KIT), Karlsruhe, Germany
| | - Sepand Rastegar
- Institute of Biological and Chemical Systems-Biological Information Processing (IBCS-BIP), Karlsruhe Institute of Technology (KIT), Karlsruhe, Germany
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38
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McCallum S, Obata Y, Fourli E, Boeing S, Peddie CJ, Xu Q, Horswell S, Kelsh RN, Collinson L, Wilkinson D, Pin C, Pachnis V, Heanue TA. Enteric glia as a source of neural progenitors in adult zebrafish. eLife 2020; 9:e56086. [PMID: 32851974 PMCID: PMC7521928 DOI: 10.7554/elife.56086] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2020] [Accepted: 08/26/2020] [Indexed: 12/23/2022] Open
Abstract
The presence and identity of neural progenitors in the enteric nervous system (ENS) of vertebrates is a matter of intense debate. Here, we demonstrate that the non-neuronal ENS cell compartment of teleosts shares molecular and morphological characteristics with mammalian enteric glia but cannot be identified by the expression of canonical glial markers. However, unlike their mammalian counterparts, which are generally quiescent and do not undergo neuronal differentiation during homeostasis, we show that a relatively high proportion of zebrafish enteric glia proliferate under physiological conditions giving rise to progeny that differentiate into enteric neurons. We also provide evidence that, similar to brain neural stem cells, the activation and neuronal differentiation of enteric glia are regulated by Notch signalling. Our experiments reveal remarkable similarities between enteric glia and brain neural stem cells in teleosts and open new possibilities for use of mammalian enteric glia as a potential source of neurons to restore the activity of intestinal neural circuits compromised by injury or disease.
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Affiliation(s)
- Sarah McCallum
- Development and Homeostasis of the Nervous System Laboratory, The Francis Crick InstituteLondonUnited Kingdom
| | - Yuuki Obata
- Development and Homeostasis of the Nervous System Laboratory, The Francis Crick InstituteLondonUnited Kingdom
| | - Evangelia Fourli
- Development and Homeostasis of the Nervous System Laboratory, The Francis Crick InstituteLondonUnited Kingdom
| | - Stefan Boeing
- Bionformatics & Biostatistics Science Technology Platform, The Francis Crick InstituteLondonUnited Kingdom
| | - Christopher J Peddie
- Electron Microscopy Science Technology Platform, The Francis Crick InstituteLondonUnited Kingdom
| | - Qiling Xu
- Neural Development Laboratory, The Francis Crick InstituteLondonUnited Kingdom
| | - Stuart Horswell
- Bionformatics & Biostatistics Science Technology Platform, The Francis Crick InstituteLondonUnited Kingdom
| | - Robert N Kelsh
- Department of Biology and Biochemistry, University of BathBathUnited Kingdom
| | - Lucy Collinson
- Electron Microscopy Science Technology Platform, The Francis Crick InstituteLondonUnited Kingdom
| | - David Wilkinson
- Neural Development Laboratory, The Francis Crick InstituteLondonUnited Kingdom
| | - Carmen Pin
- Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, R&D, AstraZenecaCambridgeUnited Kingdom
| | - Vassilis Pachnis
- Development and Homeostasis of the Nervous System Laboratory, The Francis Crick InstituteLondonUnited Kingdom
| | - Tiffany A Heanue
- Development and Homeostasis of the Nervous System Laboratory, The Francis Crick InstituteLondonUnited Kingdom
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39
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Var SR, Byrd-Jacobs CA. Role of Macrophages and Microglia in Zebrafish Regeneration. Int J Mol Sci 2020; 21:E4768. [PMID: 32635596 PMCID: PMC7369716 DOI: 10.3390/ijms21134768] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Revised: 07/02/2020] [Accepted: 07/03/2020] [Indexed: 12/11/2022] Open
Abstract
Currently, there is no treatment for recovery of human nerve function after damage to the central nervous system (CNS), and there are limited regenerative capabilities in the peripheral nervous system. Since fish are known for their regenerative abilities, understanding how these species modulate inflammatory processes following injury has potential translational importance for recovery from damage and disease. Many diseases and injuries involve the activation of innate immune cells to clear damaged cells. The resident immune cells of the CNS are microglia, the primary cells that respond to infection and injury, and their peripheral counterparts, macrophages. These cells serve as key modulators of development and plasticity and have been shown to be important in the repair and regeneration of structure and function after injury. Zebrafish are an emerging model for studying macrophages in regeneration after injury and microglia in neurodegenerative disorders such as Parkinson's disease and Alzheimer's disease. These fish possess a high degree of neuroanatomical, neurochemical, and emotional/social behavioral resemblance with humans, serving as an ideal simulator for many pathologies. This review explores literature on macrophage and microglial involvement in facilitating regeneration. Understanding innate immune cell behavior following damage may help to develop novel methods for treating toxic and chronic inflammatory processes that are seen in trauma and disease.
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40
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Labusch M, Mancini L, Morizet D, Bally-Cuif L. Conserved and Divergent Features of Adult Neurogenesis in Zebrafish. Front Cell Dev Biol 2020; 8:525. [PMID: 32695781 PMCID: PMC7338623 DOI: 10.3389/fcell.2020.00525] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2020] [Accepted: 06/03/2020] [Indexed: 12/14/2022] Open
Abstract
Adult neurogenesis, i.e., the generation of neurons from neural stem cells (NSCs) in the adult brain, contributes to brain plasticity in all vertebrates. It varies, however, greatly in extent, location and physiological characteristics between species. During the last decade, the teleost zebrafish (D. rerio) was increasingly used to study the molecular and cellular properties of adult NSCs, in particular as a prominent NSC population was discovered at the ventricular surface of the dorsal telencephalon (pallium), in territories homologous to the adult neurogenic niches of rodents. This model, for its specific features (large NSC population, amenability to intravital imaging, high regenerative capacity) allowed rapid progress in the characterization of basic adult NSC features. We review here these findings, with specific comparisons with the situation in rodents. We specifically discuss the cellular nature of NSCs (astroglial or neuroepithelial cells), their heterogeneities and their neurogenic lineages, and the mechanisms controlling NSC quiescence and fate choices, which all impact the neurogenic output. We further discuss the regulation of NSC activity in response to physiological triggers and non-physiological conditions such as regenerative contexts.
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Affiliation(s)
- Miriam Labusch
- Zebrafish Neurogenetics Unit, Institut Pasteur, UMR 3738, CNRS, Team Supported by the Ligue Nationale Contre le Cancer, Paris, France.,Sorbonne Université, Collège Doctoral, Paris, France
| | - Laure Mancini
- Zebrafish Neurogenetics Unit, Institut Pasteur, UMR 3738, CNRS, Team Supported by the Ligue Nationale Contre le Cancer, Paris, France.,Sorbonne Université, Collège Doctoral, Paris, France
| | - David Morizet
- Zebrafish Neurogenetics Unit, Institut Pasteur, UMR 3738, CNRS, Team Supported by the Ligue Nationale Contre le Cancer, Paris, France.,Sorbonne Université, Collège Doctoral, Paris, France
| | - Laure Bally-Cuif
- Zebrafish Neurogenetics Unit, Institut Pasteur, UMR 3738, CNRS, Team Supported by the Ligue Nationale Contre le Cancer, Paris, France
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41
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Jurisch-Yaksi N, Yaksi E, Kizil C. Radial glia in the zebrafish brain: Functional, structural, and physiological comparison with the mammalian glia. Glia 2020; 68:2451-2470. [PMID: 32476207 DOI: 10.1002/glia.23849] [Citation(s) in RCA: 104] [Impact Index Per Article: 20.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2020] [Revised: 05/07/2020] [Accepted: 05/13/2020] [Indexed: 02/01/2023]
Abstract
The neuroscience community has witnessed a tremendous expansion of glia research. Glial cells are now on center stage with leading roles in the development, maturation, and physiology of brain circuits. Over the course of evolution, glia have highly diversified and include the radial glia, astroglia or astrocytes, microglia, oligodendrocytes, and ependymal cells, each having dedicated functions in the brain. The zebrafish, a small teleost fish, is no exception to this and recent evidences point to evolutionarily conserved roles for glia in the development and physiology of its nervous system. Due to its small size, transparency, and genetic amenability, the zebrafish has become an increasingly prominent animal model for brain research. It has enabled the study of neural circuits from individual cells to entire brains, with a precision unmatched in other vertebrate models. Moreover, its high neurogenic and regenerative potential has attracted a lot of attention from the research community focusing on neural stem cells and neurodegenerative diseases. Hence, studies using zebrafish have the potential to provide fundamental insights about brain development and function, and also elucidate neural and molecular mechanisms of neurological diseases. We will discuss here recent discoveries on the diverse roles of radial glia and astroglia in neurogenesis, in modulating neuronal activity and in regulating brain homeostasis at the brain barriers. By comparing insights made in various animal models, particularly mammals and zebrafish, our goal is to highlight the similarities and differences in glia biology among species, which could set new paradigms relevant to humans.
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Affiliation(s)
- Nathalie Jurisch-Yaksi
- Kavli Institute for Systems Neuroscience and Centre for Neural Computation, Norwegian University of Science and Technology, Trondheim, Norway.,Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway.,Department of Neurology and Clinical Neurophysiology, St Olav University Hospital, Trondheim, Norway
| | - Emre Yaksi
- Kavli Institute for Systems Neuroscience and Centre for Neural Computation, Norwegian University of Science and Technology, Trondheim, Norway
| | - Caghan Kizil
- German Center for Neurodegenerative Diseases (DZNE), Helmholtz Association, Dresden, Germany.,Center for Molecular and Cellular Bioengineering (CMCB), TU Dresden, Dresden, Germany
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42
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Mashkaryan V, Siddiqui T, Popova S, Cosacak MI, Bhattarai P, Brandt K, Govindarajan N, Petzold A, Reinhardt S, Dahl A, Lefort R, Kizil C. Type 1 Interleukin-4 Signaling Obliterates Mouse Astroglia in vivo but Not in vitro. Front Cell Dev Biol 2020; 8:114. [PMID: 32181251 PMCID: PMC7057913 DOI: 10.3389/fcell.2020.00114] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2019] [Accepted: 02/10/2020] [Indexed: 12/11/2022] Open
Abstract
Recent findings suggest that reduced neurogenesis could be one of the underlying reasons for the exacerbated neuropathology in humans, thus restoring the neural stem cell proliferation and neurogenesis could help to circumvent some pathological aspects of Alzheimer’s disease. We recently identified Interleukin-4/STAT6 signaling as a neuron–glia crosstalk mechanism that enables glial proliferation and neurogenesis in adult zebrafish brain and 3D cultures of human astroglia, which manifest neurogenic properties. In this study, by using single cell sequencing in the APP/PS1dE9 mouse model of AD, we found that IL4 receptor (Il4r) is not expressed in mouse astroglia and IL4 signaling is not active in these cells. We tested whether activating IL4/STAT6 signaling would enhance cell proliferation and neurogenesis in healthy and disease conditions. Lentivirus-mediated expression of IL4R or constitutively active STAT6VT impaired the survival capacity of mouse astroglia in vivo but not in vitro. These results suggest that the adult mouse brain generates a non-permissive environment that dictates a negative effect of IL4 signaling on astroglial survival and neurogenic properties in contrast to zebrafish brains and in vitro mammalian cell cultures. Our findings that IL4R signaling in dentate gyrus (DG) of adult mouse brain impinges on the survival of DG cells implicate an evolutionary mechanism that might underlie the loss of neuroregenerative ability of the brain, which might be utilized for basic and clinical aspects for neurodegenerative diseases.
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Affiliation(s)
- Violeta Mashkaryan
- German Center for Neurodegenerative Diseases Dresden, Helmholtz Association, Dresden, Germany
| | - Tohid Siddiqui
- German Center for Neurodegenerative Diseases Dresden, Helmholtz Association, Dresden, Germany
| | - Stanislava Popova
- German Center for Neurodegenerative Diseases Dresden, Helmholtz Association, Dresden, Germany
| | - Mehmet Ilyas Cosacak
- German Center for Neurodegenerative Diseases Dresden, Helmholtz Association, Dresden, Germany
| | - Prabesh Bhattarai
- German Center for Neurodegenerative Diseases Dresden, Helmholtz Association, Dresden, Germany
| | - Kerstin Brandt
- German Center for Neurodegenerative Diseases Dresden, Helmholtz Association, Dresden, Germany
| | - Nambirajan Govindarajan
- German Center for Neurodegenerative Diseases Dresden, Helmholtz Association, Dresden, Germany
| | - Andreas Petzold
- DRESDEN-Concept Genome Center, Center for Molecular and Cellular Bioengineering, TU Dresden, Dresden, Germany
| | - Susanne Reinhardt
- DRESDEN-Concept Genome Center, Center for Molecular and Cellular Bioengineering, TU Dresden, Dresden, Germany
| | - Andreas Dahl
- DRESDEN-Concept Genome Center, Center for Molecular and Cellular Bioengineering, TU Dresden, Dresden, Germany
| | - Roger Lefort
- Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY, United States
| | - Caghan Kizil
- German Center for Neurodegenerative Diseases Dresden, Helmholtz Association, Dresden, Germany.,Center for Regenerative Therapies Dresden, Center for Molecular and Cellular Bioengineering, TU Dresden, Dresden, Germany
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43
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Zambusi A, Pelin Burhan Ö, Di Giaimo R, Schmid B, Ninkovic J. Granulins Regulate Aging Kinetics in the Adult Zebrafish Telencephalon. Cells 2020; 9:E350. [PMID: 32028681 PMCID: PMC7072227 DOI: 10.3390/cells9020350] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2019] [Revised: 01/31/2020] [Accepted: 01/31/2020] [Indexed: 12/26/2022] Open
Abstract
Granulins (GRN) are secreted factors that promote neuronal survival and regulate inflammation in various pathological conditions. However, their roles in physiological conditions in the brain remain poorly understood. To address this knowledge gap, we analysed the telencephalon in Grn-deficient zebrafish and identified morphological and transcriptional changes in microglial cells, indicative of a pro-inflammatory phenotype in the absence of any insult. Unexpectedly, activated mutant microglia shared part of their transcriptional signature with aged human microglia. Furthermore, transcriptome profiles of the entire telencephali isolated from young Grn-deficient animals showed remarkable similarities with the profiles of the telencephali isolated from aged wildtype animals. Additionally, 50% of differentially regulated genes during aging were regulated in the telencephalon of young Grn-deficient animals compared to their wildtype littermates. Importantly, the telencephalon transcriptome in young Grn-deficent animals changed only mildly with aging, further suggesting premature aging of Grn-deficient brain. Indeed, Grn loss led to decreased neurogenesis and oligodendrogenesis, and to shortening of telomeres at young ages, to an extent comparable to that observed during aging. Altogether, our data demonstrate a role of Grn in regulating aging kinetics in the zebrafish telencephalon, thus providing a valuable tool for the development of new therapeutic approaches to treat age-associated pathologies.
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Affiliation(s)
- Alessandro Zambusi
- Institute of Stem Cell Research, Helmholtz Center Munich, 85764 Neuherberg, Germany
- Graduate School of Systemic Neuroscience; Biomedical Center, Faculty of Medicine, LMU Munich, 82152 Planegg, Germany
| | - Özge Pelin Burhan
- German Center for Neurodegenerative Diseases (DZNE), 81377 München, Germany; (Ö.P.B.); (B.S.)
| | - Rossella Di Giaimo
- Department of Biology, University of Naples Federico II, 80134 Naples, Italy;
| | - Bettina Schmid
- German Center for Neurodegenerative Diseases (DZNE), 81377 München, Germany; (Ö.P.B.); (B.S.)
| | - Jovica Ninkovic
- Institute of Stem Cell Research, Helmholtz Center Munich, 85764 Neuherberg, Germany
- Graduate School of Systemic Neuroscience; Biomedical Center, Faculty of Medicine, LMU Munich, 82152 Planegg, Germany
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44
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Zambusi A, Ninkovic J. Regeneration of the central nervous system-principles from brain regeneration in adult zebrafish. World J Stem Cells 2020; 12:8-24. [PMID: 32110272 PMCID: PMC7031763 DOI: 10.4252/wjsc.v12.i1.8] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2019] [Revised: 11/25/2019] [Accepted: 12/16/2019] [Indexed: 02/06/2023] Open
Abstract
Poor recovery of neuronal functions is one of the most common healthcare challenges for patients with different types of brain injuries and/or neurodegenerative diseases. Therapeutic interventions face two major challenges: (1) How to generate neurons de novo to replenish the neuronal loss caused by injuries or neurodegeneration (restorative neurogenesis) and (2) How to prevent or limit the secondary tissue damage caused by long-term accumulation of glial cells, including microglia, at injury site (glial scar). In contrast to mammals, zebrafish have extensive regenerative capacity in numerous vital organs, including the brain, thus making them a valuable model to improve the existing therapeutic approaches for human brain repair. In response to injuries to the central nervous system (CNS), zebrafish have developed specific mechanisms to promote the recovery of the lost tissue architecture and functionality of the damaged CNS. These mechanisms include the activation of a restorative neurogenic program in a specific set of glial cells (ependymoglia) and the resolution of both the glial scar and inflammation, thus enabling proper neuronal specification and survival. In this review, we discuss the cellular and molecular mechanisms underlying the regenerative ability in the adult zebrafish brain and conclude with the potential applicability of these mechanisms in repair of the mammalian CNS.
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Affiliation(s)
- Alessandro Zambusi
- Helmholtz Center Munich, Biomedical Center, Inst Stem Cell Res, Institute of Stem Cell Research, Department of Cell Biology and Anatomy, University of Munich, Planegg 82152, Germany
| | - Jovica Ninkovic
- Helmholtz Center Munich, Biomedical Center, Inst Stem Cell Res, Institute of Stem Cell Research, Department of Cell Biology and Anatomy, University of Munich, Planegg 82152, Germany
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45
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Neuron-glia interaction through Serotonin-BDNF-NGFR axis enables regenerative neurogenesis in Alzheimer's model of adult zebrafish brain. PLoS Biol 2020; 18:e3000585. [PMID: 31905199 PMCID: PMC6964913 DOI: 10.1371/journal.pbio.3000585] [Citation(s) in RCA: 86] [Impact Index Per Article: 17.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2019] [Revised: 01/16/2020] [Accepted: 12/12/2019] [Indexed: 11/23/2022] Open
Abstract
It was recently suggested that supplying the brain with new neurons could counteract Alzheimer’s disease (AD). This provocative idea requires further testing in experimental models in which the molecular basis of disease-induced neuronal regeneration could be investigated. We previously found that zebrafish stimulates neural stem cell (NSC) plasticity and neurogenesis in AD and could help to understand the mechanisms to be harnessed for developing new neurons in diseased mammalian brains. Here, by performing single-cell transcriptomics, we found that amyloid toxicity-induced interleukin-4 (IL4) promotes NSC proliferation and neurogenesis by suppressing the tryptophan metabolism and reducing the production of serotonin. NSC proliferation was suppressed by serotonin via down-regulation of brain-derived neurotrophic factor (BDNF)-expression in serotonin-responsive periventricular neurons. BDNF enhances NSC plasticity and neurogenesis via nerve growth factor receptor A (NGFRA)/ nuclear factor 'kappa-light-chain-enhancer' of activated B-cells (NFkB) signaling in zebrafish but not in rodents. Collectively, our results suggest a complex neuron-glia interaction that regulates regenerative neurogenesis after AD conditions in zebrafish. Can regeneration of lost neurons counteract neurodegenerative disease? This study shows that serotonergic neurons alter neural stem cell proliferation and neurogenesis via a complex neuron-glia interaction involving interleukin-4, BDNF and NGF receptor in a zebrafish model of Alzheimer's disease.
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46
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Ceci M, Mariano V, Romano N. Zebrafish as a translational regeneration model to study the activation of neural stem cells and role of their environment. Rev Neurosci 2019; 30:45-66. [PMID: 30067512 DOI: 10.1515/revneuro-2018-0020] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2018] [Accepted: 04/27/2018] [Indexed: 02/07/2023]
Abstract
The review is an overview of the current knowledge of neuronal regeneration properties in mammals and fish. The ability to regenerate the damaged parts of the nervous tissue has been demonstrated in all vertebrates. Notably, fish and amphibians have the highest capacity for neurogenesis, whereas reptiles and birds are able to only regenerate specific regions of the brain, while mammals have reduced capacity for neurogenesis. Zebrafish (Danio rerio) is a promising model of study because lesions in the brain or complete cross-section of the spinal cord are followed by an effective neuro-regeneration that successfully restores the motor function. In the brain and the spinal cord of zebrafish, stem cell activity is always able to re-activate the molecular programs required for central nervous system regeneration. In mammals, traumatic brain injuries are followed by reduced neurogenesis and poor axonal regeneration, often insufficient to functionally restore the nervous tissue, while spinal injuries are not repaired at all. The environment that surrounds the stem cell niche constituted by connective tissue and stimulating factors, including pro-inflammation molecules, seems to be a determinant in triggering stem cell proliferation and/or the trans-differentiation of connective elements (mainly fibroblasts). Investigating and comparing the neuronal regeneration in zebrafish and mammals may lead to a better understanding of the mechanisms behind neurogenesis, and the failure of the regenerative response in mammals, first of all, the role of inflammation, considered the main inhibitor of the neuronal regeneration.
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Affiliation(s)
- Marcello Ceci
- Department of Ecological and Biological Sciences, University of Tuscia, largo dell'Università, I-01100 Viterbo, Italy
| | - Vittoria Mariano
- Department of Fundamental Neurosciences, University of Lausanne, CH-1005 Lausanne, Switzerland
| | - Nicla Romano
- Department of Ecological and Biological Sciences, University of Tuscia, largo dell'Università, I-01100 Viterbo, Italy
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47
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Yu S, He J. Stochastic cell-cycle entry and cell-state-dependent fate outputs of injury-reactivated tectal radial glia in zebrafish. eLife 2019; 8:48660. [PMID: 31442201 PMCID: PMC6707787 DOI: 10.7554/elife.48660] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2019] [Accepted: 08/02/2019] [Indexed: 12/22/2022] Open
Abstract
Gliosis defined as reactive changes of resident glia is the primary response of the central nervous system (CNS) to trauma. The proliferation and fate controls of injury-reactivated glia are essential but remain largely unexplored. In zebrafish optic tectum, we found that stab injury drove a subset of radial glia (RG) into the cell cycle, and surprisingly, proliferative RG responding to sequential injuries of the same site were distinct but overlapping, which was in agreement with stochastic cell-cycle entry. Single-cell RNA sequencing analysis and functional assays further revealed the involvement of Notch/Delta lateral inhibition in this stochastic cell-cycle entry. Furthermore, the long-term clonal analysis showed that proliferative RG were largely gliogenic. Notch inhibition of reactive RG, not dormant and proliferative RG, resulted in an increased production of neurons, which were short-lived. Our findings gain new insights into the proliferation and fate controls of injury-reactivated CNS glia in zebrafish. The brain contains networks of cells known as neurons that rapidly relay information from one place to another. Other brain cells called glial cells perform several roles to support and protect the neurons including holding them in position and supplying them with oxygen and other nutrients. Damage to the brain as a result of physical injuries is one of the leading causes of death and disability in people worldwide. Brain injuries generally stimulate glial cells to enter a “reactive” state to help repair the damage. However, some glial cells may start to divide and produce more glial cells instead, leading to scar-like structures in the brain that hinder the repair process. To investigate why brain injuries trigger some glial cells to divide, Yu and He systematically examined glial cells in the part of the zebrafish brain that handles vision, known as the optic tectum. The experiments showed that a physical injury stimulated some of the glial cells to divide. Repeated injuries to the same part of the brain did not always stimulate the same glial cells to divide, suggesting that this process happens in random cells. Further experiments revealed that molecules involved in a signaling pathway known as Notch signaling were released from some brain cells and inhibited neighboring glial cells from dividing to make new glial cells. Unexpectedly, inhibiting Notch signaling after a brain injury caused some of the glial cells that were in the reactive state to divide to produce neurons instead of glial cells. Understanding how the brain responds to injury may help researchers develop new therapies that may benefit human patients in future. The next steps following on from this work will be to find out whether glial cells in humans and other mammals work in the same way as glial cells in zebrafish.
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Affiliation(s)
- Shuguang Yu
- State Key Laboratory of Neuroscience, Institute of Neuroscience, Shanghai Institutes for Biological Sciences, Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, China.,University of Chinese Academy of Sciences, Beijing, China
| | - Jie He
- State Key Laboratory of Neuroscience, Institute of Neuroscience, Shanghai Institutes for Biological Sciences, Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, China
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48
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49
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Stolper J, Ambrosio EM, Danciu DP, Buono L, Elliott DA, Naruse K, Martínez-Morales JR, Marciniak-Czochra A, Centanin L. Stem cell topography splits growth and homeostatic functions in the fish gill. eLife 2019; 8:e43747. [PMID: 31090541 PMCID: PMC6534379 DOI: 10.7554/elife.43747] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2018] [Accepted: 05/14/2019] [Indexed: 11/13/2022] Open
Abstract
While lower vertebrates contain adult stem cells (aSCs) that maintain homeostasis and drive un-exhaustive organismal growth, mammalian aSCs display mainly the homeostatic function. Here, we use lineage analysis in the medaka fish gill to address aSCs and report separate stem cell populations for homeostasis and growth. These aSCs are fate-restricted during the entire post-embryonic life and even during re-generation paradigms. We use chimeric animals to demonstrate that p53 mediates growth coordination among fate-restricted aSCs, suggesting a hierarchical organisation among lineages in composite organs like the fish gill. Homeostatic and growth aSCs are clonal but differ in their topology; modifications in tissue architecture can convert the homeostatic zone into a growth zone, indicating a leading role for the physical niche defining stem cell output. We hypothesise that physical niches are main players to restrict aSCs to a homeostatic function in animals with fixed adult size.
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Affiliation(s)
- Julian Stolper
- Centre for Organismal StudiesHeidelberg UniversityHeidelbergGermany
- Murdoch Children’s Research InstituteRoyal Children’s HospitalParkvilleAustralia
| | | | | | - Lorena Buono
- Centro Andaluz de Biología del DesarrolloUniversidad Pablo de OlavideSevilleSpain
| | - David A Elliott
- Murdoch Children’s Research InstituteRoyal Children’s HospitalParkvilleAustralia
| | - Kiyoshi Naruse
- Laboratory of BioresourcesNational Institute for Basic Biology, National Institutes of Natural SciencesOkazakiJapan
| | | | - Anna Marciniak-Czochra
- Institute of Applied MathematicsHeidelberg UniversityHeidelbergGermany
- Bioquant CenterHeidelberg UniversityHeidelbergGermany
| | - Lazaro Centanin
- Centre for Organismal StudiesHeidelberg UniversityHeidelbergGermany
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50
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Lust K, Tanaka EM. A Comparative Perspective on Brain Regeneration in Amphibians and Teleost Fish. Dev Neurobiol 2019; 79:424-436. [PMID: 30600647 PMCID: PMC6618004 DOI: 10.1002/dneu.22665] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2018] [Revised: 12/20/2018] [Accepted: 12/26/2018] [Indexed: 01/16/2023]
Abstract
Regeneration of lost cells in the central nervous system, especially the brain, is present to varying degrees in different species. In mammals, neuronal cell death often leads to glial cell hypertrophy, restricted proliferation, and formation of a gliotic scar, which prevents neuronal regeneration. Conversely, amphibians such as frogs and salamanders and teleost fish possess the astonishing capacity to regenerate lost cells in several regions of their brains. While frogs lose their regenerative abilities after metamorphosis, teleost fish and salamanders are known to possess regenerative competence even throughout adulthood. In the last decades, substantial progress has been made in our understanding of the cellular and molecular mechanisms of brain regeneration in amphibians and fish. But how similar are the means of brain regeneration in these different species? In this review, we provide an overview of common and distinct aspects of brain regeneration in frog, salamander, and teleost fish species: from the origin of regenerated cells to the functional recovery of behaviors.
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Affiliation(s)
- Katharina Lust
- Research Institute of Molecular Pathology (IMP)Vienna Biocenter (VBC)ViennaAustria
| | - Elly M. Tanaka
- Research Institute of Molecular Pathology (IMP)Vienna Biocenter (VBC)ViennaAustria
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