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Saloni, Sachan M, Rahul, Verma RS, Patel GK. SOXs: Master architects of development and versatile emulators of oncogenesis. Biochim Biophys Acta Rev Cancer 2025; 1880:189295. [PMID: 40058508 DOI: 10.1016/j.bbcan.2025.189295] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2024] [Revised: 02/26/2025] [Accepted: 03/03/2025] [Indexed: 03/22/2025]
Abstract
Transcription factors regulate a variety of events and maintain cellular homeostasis. Several transcription factors involved in embryonic development, has been shown to be closely associated with carcinogenesis when deregulated. Sry-like high mobility group box (SOX) proteins are potential transcription factors which are evolutionarily conserved. They regulate downstream genes to determine cell fate, via various signaling pathways and cellular processes essential for tissue and organ development. Dysregulation of SOXs has been reported to promote or suppress tumorigenesis by modulating cellular reprogramming, growth, proliferation, angiogenesis, metastasis, apoptosis, immune modulation, lineage plasticity, maintenance of the stem cell pool, therapy resistance and cancer relapse. This review provides a crucial understanding of the molecular mechanism by which SOXs play multifaceted roles in embryonic development and carcinogenesis. It also highlights their potential in advancing therapeutic strategies aimed at targeting SOXs and their downstream effectors in various malignancies.
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Affiliation(s)
- Saloni
- Cancer and Stem Cell Laboratory, Department of Biotechnology, Motilal Nehru National Institute of Technology Allahabad, Prayagraj 211004, India
| | - Manisha Sachan
- Department of Biotechnology, Motilal Nehru National Institute of Technology Allahabad, Prayagraj 211004, India
| | - Rahul
- Department of Surgical Gastroenterology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow 226014, India
| | - Rama Shanker Verma
- Department of Biotechnology, Motilal Nehru National Institute of Technology Allahabad, Prayagraj 211004, India.
| | - Girijesh Kumar Patel
- Cancer and Stem Cell Laboratory, Department of Biotechnology, Motilal Nehru National Institute of Technology Allahabad, Prayagraj 211004, India.
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Yao M, Zhu X, Chen YC, Yang GH, Ao P. Exploring Multi-Target Therapeutic Strategies for Glioblastoma via Endogenous Network Modeling. Int J Mol Sci 2025; 26:3283. [PMID: 40244148 PMCID: PMC11989339 DOI: 10.3390/ijms26073283] [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: 01/14/2025] [Revised: 03/25/2025] [Accepted: 03/29/2025] [Indexed: 04/18/2025] Open
Abstract
Medical treatment of glioblastoma presents a significant challenge. A conventional medication has limited effectiveness, and a single-target therapy is usually effective only in the early stage of the treatment. Recently, there has been increasing focus on multi-target therapies, but the vast range of possible combinations makes clinical experimentation and implementation difficult. From the perspective of systems biology, this study conducted simulations for multi-target glioblastoma therapy based on dynamic analysis of previously established endogenous networks, validated with glioblastoma single-cell RNA sequencing data. Several potentially effective target combinations were identified. The findings also highlight the necessity of multi-target rather than single-target intervention strategies in cancer treatment, as well as the promise in clinical applications and personalized therapies.
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Affiliation(s)
- Mengchao Yao
- Shanghai Center for Quantitative Life Sciences and Physics Department, Shanghai University, Shanghai 200444, China;
| | - Xiaomei Zhu
- Shanghai Key Laboratory of Modern Optical System, School of Optical-Electrical and Computer Engineering, University of Shanghai for Science and Technology, Shanghai 200444, China
| | - Yong-Cong Chen
- Shanghai Center for Quantitative Life Sciences and Physics Department, Shanghai University, Shanghai 200444, China;
| | - Guo-Hong Yang
- Department of Physics, Shanghai University, Shanghai 200444, China;
| | - Ping Ao
- College of Biomedical Engineering, Sichuan University, Chengdu 610065, China
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Sun B, Stamou MI, Stockman SL, Campbell MB, Plummer L, Salnikov KB, Kotan LD, Topaloglu AK, Hisama FM, Davis EE, Seminara SB, Balasubramanian R. Expanding the Spectrum of Endocrine Abnormalities Associated With SOX11-related Disorders. J Clin Endocrinol Metab 2025; 110:1044-1052. [PMID: 39290158 DOI: 10.1210/clinem/dgae620] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2024] [Revised: 08/28/2024] [Accepted: 09/13/2024] [Indexed: 09/19/2024]
Abstract
CONTEXT SOX11 variants cause Coffin-Siris syndrome, characterized by developmental delay, hypogonadotropic hypogonadism, and skeletal and facial defects. OBJECTIVE To examine the contribution of SOX11 variants to the pathogenesis of idiopathic hypogonadotropic hypogonadism (IHH), a disorder caused by hypothalamic GnRH deficiency. SETTING The Reproductive Endocrine Unit and the Pediatric Endocrinology Division, Massachusetts General Hospital. PATIENTS OR OTHER PARTICIPANTS A cohort of 1810 unrelated IHH probands. INTERVENTIONS Exome sequencing data from the entire cohort were examined for SOX11 rare single nucleotide variants (SNVs) (minor allele frequency in the gnomAD database <0.1%). Rare SOX11 variant association testing was performed between the IHH and gnomAD population. Phenotyping of individuals harboring pathogenic/likely pathogenic SNVs (determined by the American College of Medical Genetics criteria) was performed. MAIN OUTCOMES/RESULTS Four pathogenic SOX11 SNVs were identified in 5 IHH probands. The IHH cohort was enriched for SOX11 protein truncating SNVs (frameshift/nonsense) across the entire protein (2 SNVs in 3 IHH cases [p.S303X (de novo); p.S345Afs*13]; P = .0004981) and for SOX11 missense SNVs within the SOX11 high-mobility group domain (2 SNVs in 2 IHH cases p.G84D [de novo]; p.P114S; P = .00313922). The phenotypic spectrum of SOX11 variant carriers revealed additional endocrine defects including anosmic and normosmic forms of IHH, GH deficiency, pituitary and hypothalamic structural defects, and hypothyroidism. A pathogenic SOX11 SNV was also identified in a patient with functional hypogonadotropic hypogonadism (p.R100Q). Coffin-Siris syndrome-associated features were present in 4/5 probands. CONCLUSION Deleterious SOX11 variants cause IHH and other pituitary hormone deficiencies, suggesting that the human SOX11-associated disorder may stem from both hypothalamic and pituitary level defects.
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Affiliation(s)
- Bang Sun
- Reproductive Endocrine Unit, Endocrine Division, Massachusetts General Hospital, Boston, MA 02114, USA
| | - Maria I Stamou
- Reproductive Endocrine Unit, Endocrine Division, Massachusetts General Hospital, Boston, MA 02114, USA
| | - Sara L Stockman
- Reproductive Endocrine Unit, Endocrine Division, Massachusetts General Hospital, Boston, MA 02114, USA
| | - Mark B Campbell
- Reproductive Endocrine Unit, Endocrine Division, Massachusetts General Hospital, Boston, MA 02114, USA
| | - Lacey Plummer
- Reproductive Endocrine Unit, Endocrine Division, Massachusetts General Hospital, Boston, MA 02114, USA
| | - Kathryn B Salnikov
- Reproductive Endocrine Unit, Endocrine Division, Massachusetts General Hospital, Boston, MA 02114, USA
| | - Leman Damla Kotan
- Division of Pediatric Endocrinology, Faculty of Medicine, Cukurova University, Adana, 01250, Turkey
| | - A Kemal Topaloglu
- Division of Pediatric Endocrinology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02113, USA
| | - Fuki M Hisama
- Division of Medical Genetics, Department of Medicine, University of Washington School of Medicine, Seattle, WA 98195, USA
| | - Erica E Davis
- Advanced Center for Translational and Genetic Medicine, Stanley Manne Children's Research Institute, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL 60611, USA
- Department of Pediatrics and Department of Cell and Developmental Biology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
| | - Stephanie B Seminara
- Reproductive Endocrine Unit, Endocrine Division, Massachusetts General Hospital, Boston, MA 02114, USA
| | - Ravikumar Balasubramanian
- Reproductive Endocrine Unit, Endocrine Division, Massachusetts General Hospital, Boston, MA 02114, USA
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Wu Z, Han T, Dong Y, Ying W, Fang H, Liu Y, Song P, Shen C. Acid-sensing ion channel-1 contributes to the failure of myelin sheath regeneration following spinal cord injury by transcellular delivery of PGE2. Cell Mol Biol Lett 2024; 29:149. [PMID: 39627718 PMCID: PMC11616324 DOI: 10.1186/s11658-024-00672-9] [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: 06/29/2024] [Accepted: 11/20/2024] [Indexed: 12/06/2024] Open
Abstract
BACKGROUND Traumatic injuries to spinal cord lead to severe motor, sensory, and autonomic dysfunction. The accumulation of inhibitory compounds plays a pivotal role in the secondary damage to sparing neural tissue and the failure of axonal regeneration and remyelination. Acid-sensing ion channel-1(ASIC1A) is widely activated following neurotrauma, including spinal cord injury (SCI). However, its role in SCI remains elusive. METHODS The effects of acidic environment on the differentiation and genes changes of neural stem cells (NSCs) were assessed by immunofluorescence staining and RNA-sequencing analysis, respectively. The expression of ASIC1A and prostaglandin endoperoxide synthase 2 (PTGS2) were detected by western blot and immunofluorescence staining. The concentration of prostaglandin E2 (PGE2) within NSC-derived extracellular vesicles were evaluated by ELISA. Small-interfering RNAs (siRNAs) were used to knock down Asic1a and Ptgs2 expression in NSCs. The myelin sheath regeneration and axonal remyelination in rats and Asic1a-KO mice were assessed by immunofluorescence staining. RESULTS Following injury to the spinal cord, ASIC1A was found to be colocalized and upregulated in NSCs. ASIC1A activation prevents the differentiation of NSCs into oligodendrocytes by upregulating PTGS2, which leads to increased production and release of PGE2 within extracellular vesicles (EVs). ASIC1A or PTGS2 deficiency in NSCs counters the ASIC1A-related effects on mediating NSC differentiation by reducing PGE2 expression within NSC-derived EVs. Furthermore, intervention in ASIC1A signaling by administration of ASIC1A inhibitors or genetic deletion of ASIC1A demonstrated a pronounced advantage in enhancing myelin sheath regeneration and axonal remyelination. CONCLUSIONS The activation of ASIC1A prevents NSC differentiation into oligodendrocytes via the transcellular NSC-to-NSC delivery of PGE2, resulting in the failure of myelin sheath regeneration and axonal remyelination following SCI. The inhibition of ASIC1A presents a promising therapeutic strategy for the treatment of SCI.
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Affiliation(s)
- Zuomeng Wu
- Department of Orthopedics (Spinal Surgery), The First Affiliated Hospital of Anhui Medical University, Hefei, 230032, People's Republic of China
- Laboratory of Spinal and Spinal Cord Injury Regeneration and Repair, The First Affiliated Hospital of Anhui Medical University, Hefei, 230032, People's Republic of China
| | - Tianyu Han
- Department of Orthopedics (Spinal Surgery), The First Affiliated Hospital of Anhui Medical University, Hefei, 230032, People's Republic of China
- Laboratory of Spinal and Spinal Cord Injury Regeneration and Repair, The First Affiliated Hospital of Anhui Medical University, Hefei, 230032, People's Republic of China
| | - Yixiang Dong
- Department of Orthopedics (Spinal Surgery), The First Affiliated Hospital of Anhui Medical University, Hefei, 230032, People's Republic of China
- Laboratory of Spinal and Spinal Cord Injury Regeneration and Repair, The First Affiliated Hospital of Anhui Medical University, Hefei, 230032, People's Republic of China
| | - Wang Ying
- Department of Medical Imaging, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Huang Fang
- Department of Orthopedics (Spinal Surgery), The First Affiliated Hospital of USTC, Hefei, 230032, People's Republic of China
| | - Yunlei Liu
- Department of Clinical Laboratory, The First Affiliated Hospital of Anhui Medical University, Hefei, 230032, People's Republic of China
| | - Peiwen Song
- Department of Orthopedics (Spinal Surgery), The First Affiliated Hospital of Anhui Medical University, Hefei, 230032, People's Republic of China.
- Laboratory of Spinal and Spinal Cord Injury Regeneration and Repair, The First Affiliated Hospital of Anhui Medical University, Hefei, 230032, People's Republic of China.
| | - Cailiang Shen
- Department of Orthopedics (Spinal Surgery), The First Affiliated Hospital of Anhui Medical University, Hefei, 230032, People's Republic of China.
- Laboratory of Spinal and Spinal Cord Injury Regeneration and Repair, The First Affiliated Hospital of Anhui Medical University, Hefei, 230032, People's Republic of China.
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Yao M, Su Y, Xiong R, Zhang X, Zhu X, Chen YC, Ao P. Deciphering the topological landscape of glioma using a network theory framework. Sci Rep 2024; 14:26724. [PMID: 39496747 PMCID: PMC11535471 DOI: 10.1038/s41598-024-77856-y] [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: 01/14/2024] [Accepted: 10/25/2024] [Indexed: 11/06/2024] Open
Abstract
Glioma stem cells have been recognized as key players in glioma recurrence and therapeutic resistance, presenting a promising target for novel treatments. However, the limited understanding of the role glioma stem cells play in the glioma hierarchy has drawn controversy and hindered research translation into therapies. Despite significant advances in our understanding of gene regulatory networks, the dynamics of these networks and their implications for glioma remain elusive. This study employs a systemic theoretical perspective to integrate experimental knowledge into a core endogenous network model for glioma, thereby elucidating its energy landscape through network dynamics computation. The model identifies two stable states corresponding to astrocytic-like and oligodendrocytic-like tumor cells, connected by a transition state with the feature of high stemness, which serves as one of the energy barriers between astrocytic-like and oligodendrocytic-like states, indicating the instability of glioma stem cells in vivo. We also obtained various stable states further supporting glioma's multicellular origins and uncovered a group of transition states that could potentially induce tumor heterogeneity and therapeutic resistance. This research proposes that the transition states linking both glioma stable states are central to glioma heterogeneity and therapy resistance. Our approach may contribute to the advancement of glioma therapy by offering a novel perspective on the complex landscape of glioma biology.
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Affiliation(s)
- Mengchao Yao
- Shanghai Center for Quantitative Life Sciences and Physics Department, Shanghai University, Shanghai, China
| | - Yang Su
- Shanghai Center for Quantitative Life Sciences and Physics Department, Shanghai University, Shanghai, China
| | - Ruiqi Xiong
- Shanghai Center for Quantitative Life Sciences and Physics Department, Shanghai University, Shanghai, China
| | - Xile Zhang
- Shanghai Center for Quantitative Life Sciences and Physics Department, Shanghai University, Shanghai, China
- Shanghai Shibei High School, Shanghai, China
| | - Xiaomei Zhu
- Shanghai Key Laboratory of Modern Optical System, School of Optical-Electrical and Computer Engineering, University of Shanghai for Science and Technology, Shanghai, China
| | - Yong-Cong Chen
- Shanghai Center for Quantitative Life Sciences and Physics Department, Shanghai University, Shanghai, China.
| | - Ping Ao
- College of Biomedical Engineering, Sichuan University, Chengdu, Sichuan Province, China.
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Poole RJ, Flames N, Cochella L. Neurogenesis in Caenorhabditis elegans. Genetics 2024; 228:iyae116. [PMID: 39167071 PMCID: PMC11457946 DOI: 10.1093/genetics/iyae116] [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: 05/28/2024] [Accepted: 06/24/2024] [Indexed: 08/23/2024] Open
Abstract
Animals rely on their nervous systems to process sensory inputs, integrate these with internal signals, and produce behavioral outputs. This is enabled by the highly specialized morphologies and functions of neurons. Neuronal cells share multiple structural and physiological features, but they also come in a large diversity of types or classes that give the nervous system its broad range of functions and plasticity. This diversity, first recognized over a century ago, spurred classification efforts based on morphology, function, and molecular criteria. Caenorhabditis elegans, with its precisely mapped nervous system at the anatomical level, an extensive molecular description of most of its neurons, and its genetic amenability, has been a prime model for understanding how neurons develop and diversify at a mechanistic level. Here, we review the gene regulatory mechanisms driving neurogenesis and the diversification of neuron classes and subclasses in C. elegans. We discuss our current understanding of the specification of neuronal progenitors and their differentiation in terms of the transcription factors involved and ensuing changes in gene expression and chromatin landscape. The central theme that has emerged is that the identity of a neuron is defined by modules of gene batteries that are under control of parallel yet interconnected regulatory mechanisms. We focus on how, to achieve these terminal identities, cells integrate information along their developmental lineages. Moreover, we discuss how neurons are diversified postembryonically in a time-, genetic sex-, and activity-dependent manner. Finally, we discuss how the understanding of neuronal development can provide insights into the evolution of neuronal diversity.
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Affiliation(s)
- Richard J Poole
- Department of Cell and Developmental Biology, University College London, London WC1E 6BT, UK
| | - Nuria Flames
- Developmental Neurobiology Unit, Instituto de Biomedicina de Valencia IBV-CSIC, Valencia 46012, Spain
| | - Luisa Cochella
- Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
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Yang J, Zhu X, Wang F, Chen Z, Zhang Y, Chen J, Ni H, Zhang C, Zhuge Q. SOXC Enhances NGN2-Mediated Reprogramming of Glioblastoma Cells Into Neuron-Like Cells by Modulating RhoA and RAC1/CDC42 Pathway Activity. CNS Neurosci Ther 2024; 30:e70075. [PMID: 39390804 PMCID: PMC11467166 DOI: 10.1111/cns.70075] [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: 05/06/2024] [Revised: 09/04/2024] [Accepted: 09/24/2024] [Indexed: 10/12/2024] Open
Abstract
BACKGROUND Glioblastoma represents the most frequently diagnosed malignant neoplasm within the central nervous system. Human glioblastoma cells can be phenotypically reprogrammed into neuron-like cells through the forced expression of NEUROG2 and SOXC factors. NEUROG2 serves as a pioneer factor, establishing an initial framework for this transformation. However, the specific role of SOXC factors has not been fully elucidated. METHODS In this study, we used ChIP-seq to determine the potential target gene of NGN2. RNA-seq has been used to evaluate the transcriptional change during NGN2-SOX11-mediated neuron reprogramming. Immunofluorescence was used to determine the neuron reprogramming efficacy and cell proliferation ability. ChIP-qPCR, Co-IP, and Western Blot were performed to investigate the mechanism. RESULTS Our findings reveal that SOXC factors, in contrast to their previously identified function as transcriptional activators, act as transcriptional repressors. They achieve this by recruiting TRIM28 to suppress the expression of ECT2, a RhoGEF. This suppression results in the differential regulation of RhoA, RAC1, and CDC42 activities throughout the reprogramming process. We further establish that small molecules targeting RhoA and its effectors can substitute for SOXC factors in facilitating the neuronal reprogramming of glioblastoma cells. CONCLUSION These results underscore the pivotal role of SOXC factors' transcriptional repression and illuminate one of their specific downstream targets.
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Affiliation(s)
- Jianjing Yang
- Department of NeurosurgeryThe First Affiliated Hospital of Wenzhou Medical UniversityWenzhouZhejiangChina
- Zhejiang‐US Joint Laboratory for Aging and Neurological Disease ResearchThe First Affiliated Hospital of Wenzhou Medical UniversityWenzhouChina
- Zhejiang Provincial Key Laboratory of Aging and Neurological Disorder ResearchThe First Affiliated Hospital of Wenzhou Medical UniversityWenzhouChina
- Department of Molecular BiologyUniversity of Texas Southwestern Medical CenterDallasTexasUSA
- Hamon Center for Regenerative Science and MedicineUniversity of Texas Southwestern Medical CenterDallasTexasUSA
| | - Xiaohong Zhu
- Department of NeurosurgeryThe First Affiliated Hospital of Wenzhou Medical UniversityWenzhouZhejiangChina
- Zhejiang‐US Joint Laboratory for Aging and Neurological Disease ResearchThe First Affiliated Hospital of Wenzhou Medical UniversityWenzhouChina
- Zhejiang Provincial Key Laboratory of Aging and Neurological Disorder ResearchThe First Affiliated Hospital of Wenzhou Medical UniversityWenzhouChina
| | - Fan Wang
- Department of NeurosurgeryThe First Affiliated Hospital of Wenzhou Medical UniversityWenzhouZhejiangChina
- Zhejiang‐US Joint Laboratory for Aging and Neurological Disease ResearchThe First Affiliated Hospital of Wenzhou Medical UniversityWenzhouChina
- Zhejiang Provincial Key Laboratory of Aging and Neurological Disorder ResearchThe First Affiliated Hospital of Wenzhou Medical UniversityWenzhouChina
| | - Zhen Chen
- Department of NeurosurgeryThe First Affiliated Hospital of Wenzhou Medical UniversityWenzhouZhejiangChina
- Zhejiang‐US Joint Laboratory for Aging and Neurological Disease ResearchThe First Affiliated Hospital of Wenzhou Medical UniversityWenzhouChina
- Zhejiang Provincial Key Laboratory of Aging and Neurological Disorder ResearchThe First Affiliated Hospital of Wenzhou Medical UniversityWenzhouChina
| | - Ying Zhang
- Department of NeurosurgeryThe First Affiliated Hospital of Wenzhou Medical UniversityWenzhouZhejiangChina
- Zhejiang‐US Joint Laboratory for Aging and Neurological Disease ResearchThe First Affiliated Hospital of Wenzhou Medical UniversityWenzhouChina
- Zhejiang Provincial Key Laboratory of Aging and Neurological Disorder ResearchThe First Affiliated Hospital of Wenzhou Medical UniversityWenzhouChina
| | - Jiawei Chen
- Department of NeurosurgeryThe First Affiliated Hospital of Wenzhou Medical UniversityWenzhouZhejiangChina
- Zhejiang‐US Joint Laboratory for Aging and Neurological Disease ResearchThe First Affiliated Hospital of Wenzhou Medical UniversityWenzhouChina
- Zhejiang Provincial Key Laboratory of Aging and Neurological Disorder ResearchThe First Affiliated Hospital of Wenzhou Medical UniversityWenzhouChina
| | - Haoqi Ni
- Department of NeurosurgeryThe First Affiliated Hospital of Wenzhou Medical UniversityWenzhouZhejiangChina
- Zhejiang‐US Joint Laboratory for Aging and Neurological Disease ResearchThe First Affiliated Hospital of Wenzhou Medical UniversityWenzhouChina
- Zhejiang Provincial Key Laboratory of Aging and Neurological Disorder ResearchThe First Affiliated Hospital of Wenzhou Medical UniversityWenzhouChina
- Department of Molecular BiologyUniversity of Texas Southwestern Medical CenterDallasTexasUSA
- Hamon Center for Regenerative Science and MedicineUniversity of Texas Southwestern Medical CenterDallasTexasUSA
| | - Chun‐Li Zhang
- Department of Molecular BiologyUniversity of Texas Southwestern Medical CenterDallasTexasUSA
- Hamon Center for Regenerative Science and MedicineUniversity of Texas Southwestern Medical CenterDallasTexasUSA
| | - Qichuan Zhuge
- Department of NeurosurgeryThe First Affiliated Hospital of Wenzhou Medical UniversityWenzhouZhejiangChina
- Zhejiang‐US Joint Laboratory for Aging and Neurological Disease ResearchThe First Affiliated Hospital of Wenzhou Medical UniversityWenzhouChina
- Zhejiang Provincial Key Laboratory of Aging and Neurological Disorder ResearchThe First Affiliated Hospital of Wenzhou Medical UniversityWenzhouChina
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Santos CL, Weber FB, Belló-Klein A, Bobermin LD, Quincozes-Santos A. Glioprotective Effects of Sulforaphane in Hypothalamus: Focus on Aging Brain. Neurochem Res 2024; 49:2505-2518. [PMID: 38886329 DOI: 10.1007/s11064-024-04196-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2023] [Revised: 06/04/2024] [Accepted: 06/10/2024] [Indexed: 06/20/2024]
Abstract
Sulforaphane is a natural compound with neuroprotective activity, but its effects on hypothalamus remain unknown. In line with this, astrocytes are critical cells to maintain brain homeostasis, and hypothalamic astrocytes are fundamental for sensing and responding to environmental changes involved in a variety of homeostatic functions. Changes in brain functionality, particularly associated with hypothalamic astrocytes, can contribute to age-related neurochemical alterations and, consequently, neurodegenerative diseases. Thus, here, we investigated the glioprotective effects of sulforaphane on hypothalamic astrocyte cultures and hypothalamic cell suspension obtained from aged Wistar rats (24 months old). Sulforaphane showed anti-inflammatory and antioxidant properties, as well as modulated the mRNA expression of astroglial markers, such as aldehyde dehydrogenase 1 family member L1, aquaporin 4, and vascular endothelial growth factor. In addition, it increased the expression and extracellular levels of trophic factors, such as glia-derived neurotrophic factor and nerve growth factor, as well as the release of brain-derived neurotrophic factor and the mRNA of TrkA, which is a receptor associated with trophic factors. Sulforaphane also modulated the expression of classical pathways associated with glioprotection, including nuclear factor erythroid-derived 2-like 2, heme oxygenase-1, nuclear factor kappa B p65 subunit, and AMP-activated protein kinase. Finally, a cell suspension with neurons and glial cells was used to confirm the predominant effect of sulforaphane in glial cells. In summary, this study indicated the anti-aging and glioprotective activities of sulforaphane in aged astrocytes.
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Affiliation(s)
- Camila Leite Santos
- Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - Fernanda Becker Weber
- Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - Adriane Belló-Klein
- Programa de Pós-Graduação em Ciências Biológicas: Fisiologia, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
- Departamento de Fisiologia, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - Larissa Daniele Bobermin
- Programa de Pós-Graduação em Neurociências, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - André Quincozes-Santos
- Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
- Programa de Pós-Graduação em Neurociências, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
- Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
- Laboratório de Neurotoxicidade e Glioproteção (LABGLIO), Departamento de Bioquímica, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2600 - Anexo, Bairro Santa Cecília, Porto Alegre, RS, 90035-003, Brazil.
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Li H, Sun D, Zhao Z, Fang J, Li M, Lv C, Zhou W, Li N, Guo Y, Cao Z, Liu K, Chen X. Neutrophil membrane-derived nanoparticles protect traumatic brain injury via inhibiting calcium overload and scavenging ROS. J Nanobiotechnology 2024; 22:477. [PMID: 39135044 PMCID: PMC11320991 DOI: 10.1186/s12951-024-02753-5] [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: 11/06/2023] [Accepted: 08/02/2024] [Indexed: 08/15/2024] Open
Abstract
The secondary injury is more serious after traumatic brain injury (TBI) compared with primary injury. Release of excessive reactive oxygen species (ROS) and Ca2+ influx at the damaged site trigger the secondary injury. Herein, a neutrophil-like cell membrane-functionalized nanoparticle was developed to prevent ROS-associated secondary injury. NCM@MP was composed of three parts: (1) Differentiated neutrophil-like cell membrane (NCM) was synthesized, with inflammation-responsive ability to achieve effective targeting and to increase the retention time of Mn3O4 and nimodipine (MP) in deep injury brain tissue via C-X-C chemokine receptor type 4, integrin beta 1 and macrophage antigen-1. (2) Nimodipine was used to inhibit Ca2+ influx, eliminating the ROS at source. (3) Mn3O4 further eradicated the existing ROS. In addition, NCM@MP also exhibited desirable properties for T1 enhanced imaging and low toxicity which may serve as promising multifunctional nanoplatforms for precise therapies. In our study, NCM@MP obviously alleviated oxidative stress response, reduced neuroinflammation, protected blood-brain barrier integrity, relieved brain edema, promoted the regeneration of neurons, and improved the cognition of TBI mice. This study provides a promising TBI management to relieve the secondary spread of damage.
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Affiliation(s)
- Hongqing Li
- Department of Nuclear Medicine, Daping Hospital, Army Medical University, Chongqing, 400042, China
| | - Duo Sun
- Department of Nuclear Medicine, Daping Hospital, Army Medical University, Chongqing, 400042, China
| | - Zhenghuan Zhao
- College of Basic Medicine, Chongqing Medical University, Chongqing, 400016, China
| | - Jingqin Fang
- Department of Ultrasound, Daping Hospital, Army Medical University, Chongqing, 400042, China
| | - Muyao Li
- College of Basic Medicine, Chongqing Medical University, Chongqing, 400016, China
| | - Chaoqun Lv
- Department of Gastroenterology, Daping Hospital, Army Medical University, Chongqing, 400042, China
| | - Weicheng Zhou
- Department of Nuclear Medicine, Daping Hospital, Army Medical University, Chongqing, 400042, China
| | - Ning Li
- Department of Nuclear Medicine, Daping Hospital, Army Medical University, Chongqing, 400042, China
| | - Yu Guo
- Department of Radiology, Daping Hospital, Army Medical University, Chongqing, 400042, China
| | - Zhile Cao
- Department of Radiology, Daping Hospital, Army Medical University, Chongqing, 400042, China
| | - Kaijun Liu
- Department of Gastroenterology, Daping Hospital, Army Medical University, Chongqing, 400042, China.
| | - Xiao Chen
- Department of Nuclear Medicine, Daping Hospital, Army Medical University, Chongqing, 400042, China.
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10
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Sheloukhova L, Watanabe H. Evolution of glial cells: a non-bilaterian perspective. Neural Dev 2024; 19:10. [PMID: 38907299 PMCID: PMC11193209 DOI: 10.1186/s13064-024-00184-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2023] [Accepted: 06/06/2024] [Indexed: 06/23/2024] Open
Abstract
Nervous systems of bilaterian animals generally consist of two cell types: neurons and glial cells. Despite accumulating data about the many important functions glial cells serve in bilaterian nervous systems, the evolutionary origin of this abundant cell type remains unclear. Current hypotheses regarding glial evolution are mostly based on data from model bilaterians. Non-bilaterian animals have been largely overlooked in glial studies and have been subjected only to morphological analysis. Here, we provide a comprehensive overview of conservation of the bilateral gliogenic genetic repertoire of non-bilaterian phyla (Cnidaria, Placozoa, Ctenophora, and Porifera). We overview molecular and functional features of bilaterian glial cell types and discuss their possible evolutionary history. We then examine which glial features are present in non-bilaterians. Of these, cnidarians show the highest degree of gliogenic program conservation and may therefore be crucial to answer questions about glial evolution.
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Affiliation(s)
- Larisa Sheloukhova
- Evolutionary Neurobiology Unit, Okinawa Institute of Science and Technology, 1919-1 Tancha, Onna-son, Kunigami-gun, Okinawa, 904-0412, Japan
| | - Hiroshi Watanabe
- Evolutionary Neurobiology Unit, Okinawa Institute of Science and Technology, 1919-1 Tancha, Onna-son, Kunigami-gun, Okinawa, 904-0412, Japan.
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11
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Balint V, Peric M, Dacic S, Stanisavljevic Ninkovic D, Marjanovic J, Popovic J, Stevanovic M, Lazic A. The Role of SOX2 and SOX9 Transcription Factors in the Reactivation-Related Functional Properties of NT2/D1-Derived Astrocytes. Biomedicines 2024; 12:796. [PMID: 38672150 PMCID: PMC11048103 DOI: 10.3390/biomedicines12040796] [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: 12/27/2023] [Revised: 03/18/2024] [Accepted: 03/26/2024] [Indexed: 04/28/2024] Open
Abstract
Astrocytes are the main homeostatic cells in the central nervous system, with the unique ability to transform from quiescent into a reactive state in response to pathological conditions by reacquiring some precursor properties. This process is known as reactive astrogliosis, a compensatory response that mediates tissue damage and recovery. Although it is well known that SOX transcription factors drive the expression of phenotype-specific genetic programs during neurodevelopment, their roles in mature astrocytes have not been studied extensively. We focused on the transcription factors SOX2 and SOX9, shown to be re-expressed in reactive astrocytes, in order to study the reactivation-related functional properties of astrocytes mediated by those proteins. We performed an initial screening of SOX2 and SOX9 expression after sensorimotor cortex ablation injury in rats and conducted gain-of-function studies in vitro using astrocytes derived from the human NT2/D1 cell line. Our results revealed the direct involvement of SOX2 in the reacquisition of proliferation in mature NT2/D1-derived astrocytes, while SOX9 overexpression increased migratory potential and glutamate uptake in these cells. Our results imply that modulation of SOX gene expression may change the functional properties of astrocytes, which holds promise for the discovery of potential therapeutic targets in the development of novel strategies for tissue regeneration and recovery.
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Affiliation(s)
- Vanda Balint
- Laboratory for Human Molecular Genetics, Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Vojvode Stepe 444a, 11042 Belgrade, Serbia; (V.B.); (M.P.); (D.S.N.); (J.M.); (J.P.); (M.S.)
| | - Mina Peric
- Laboratory for Human Molecular Genetics, Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Vojvode Stepe 444a, 11042 Belgrade, Serbia; (V.B.); (M.P.); (D.S.N.); (J.M.); (J.P.); (M.S.)
| | - Sanja Dacic
- Institute of Physiology and Biochemistry “Ivan Djaja”, Faculty of Biology, University of Belgrade, Studentski trg 16, 11158 Belgrade, Serbia;
| | - Danijela Stanisavljevic Ninkovic
- Laboratory for Human Molecular Genetics, Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Vojvode Stepe 444a, 11042 Belgrade, Serbia; (V.B.); (M.P.); (D.S.N.); (J.M.); (J.P.); (M.S.)
| | - Jelena Marjanovic
- Laboratory for Human Molecular Genetics, Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Vojvode Stepe 444a, 11042 Belgrade, Serbia; (V.B.); (M.P.); (D.S.N.); (J.M.); (J.P.); (M.S.)
| | - Jelena Popovic
- Laboratory for Human Molecular Genetics, Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Vojvode Stepe 444a, 11042 Belgrade, Serbia; (V.B.); (M.P.); (D.S.N.); (J.M.); (J.P.); (M.S.)
| | - Milena Stevanovic
- Laboratory for Human Molecular Genetics, Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Vojvode Stepe 444a, 11042 Belgrade, Serbia; (V.B.); (M.P.); (D.S.N.); (J.M.); (J.P.); (M.S.)
- Institute of Physiology and Biochemistry “Ivan Djaja”, Faculty of Biology, University of Belgrade, Studentski trg 16, 11158 Belgrade, Serbia;
- Serbian Academy of Sciences and Arts, Kneza Mihaila 35, 11001 Belgrade, Serbia
| | - Andrijana Lazic
- Laboratory for Human Molecular Genetics, Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Vojvode Stepe 444a, 11042 Belgrade, Serbia; (V.B.); (M.P.); (D.S.N.); (J.M.); (J.P.); (M.S.)
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12
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Singleton KS, Silva-Rodriguez P, Cunningham DD, Silva EM. Xenopus Sox11 Partner Proteins and Functional Domains in Neurogenesis. Genes (Basel) 2024; 15:243. [PMID: 38397232 PMCID: PMC10887758 DOI: 10.3390/genes15020243] [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: 12/19/2023] [Revised: 02/03/2024] [Accepted: 02/05/2024] [Indexed: 02/25/2024] Open
Abstract
Sox11, a member of the SoxC family of transcription factors, has distinct functions at different times in neural development. Studies in mouse, frog, chick, and zebrafish show that Sox11 promotes neural fate, neural differentiation, and neuron maturation in the central nervous system. These diverse roles are controlled in part by spatial and temporal-specific protein interactions. However, the partner proteins and Sox11-interaction domains underlying these diverse functions are not well defined. Here, we identify partner proteins and the domains of Xenopus laevis Sox11 required for protein interaction and function during neurogenesis. Our data show that Sox11 co-localizes and interacts with Pou3f2 and Neurog2 in the anterior neural plate and in early neurons, respectively. We also demonstrate that Sox11 does not interact with Neurog1, a high-affinity partner of Sox11 in the mouse cortex, suggesting that Sox11 has species-specific partner proteins. Additionally, we determined that the N-terminus including the HMG domain of Sox11 is necessary for interaction with Pou3f2 and Neurog2, and we established a novel role for the N-terminal 46 amino acids in the specification of placodal progenitors. This is the first identification of partner proteins for Sox11 and of domains required for partner-protein interactions and distinct roles in neurogenesis.
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Affiliation(s)
- Kaela S. Singleton
- Interdisciplinary Program in Neuroscience, Georgetown University Medical Center, Washington, DC 200057, USA
| | - Pablo Silva-Rodriguez
- Department of Biology, Georgetown University, Washington, DC 20057, USA; (P.S.-R.); (D.D.C.)
| | - Doreen D. Cunningham
- Department of Biology, Georgetown University, Washington, DC 20057, USA; (P.S.-R.); (D.D.C.)
| | - Elena M. Silva
- Interdisciplinary Program in Neuroscience, Georgetown University Medical Center, Washington, DC 200057, USA
- Department of Biology, Georgetown University, Washington, DC 20057, USA; (P.S.-R.); (D.D.C.)
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13
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Fritzsch B, Schultze HP, Elliott KL. The evolution of the various structures required for hearing in Latimeria and tetrapods. IBRO Neurosci Rep 2023; 14:325-341. [PMID: 37006720 PMCID: PMC10063410 DOI: 10.1016/j.ibneur.2023.03.007] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2022] [Accepted: 03/20/2023] [Indexed: 03/30/2023] Open
Abstract
Sarcopterygians evolved around 415 Ma and have developed a unique set of features, including the basilar papilla and the cochlear aqueduct of the inner ear. We provide an overview that shows the morphological integration of the various parts needed for hearing, e.g., basilar papilla, tectorial membrane, cochlear aqueduct, lungs, and tympanic membranes. The lagena of the inner ear evolved from a common macula of the saccule several times. It is near this lagena where the basilar papilla forms in Latimeria and tetrapods. The basilar papilla is lost in lungfish, certain caecilians and salamanders, but is transformed into the cochlea of mammals. Hearing in bony fish and tetrapods involves particle motion to improve sound pressure reception within the ear but also works without air. Lungs evolved after the chondrichthyans diverged and are present in sarcopterygians and actinopterygians. Lungs open to the outside in tetraposomorph sarcopterygians but are transformed from a lung into a swim bladder in ray-finned fishes. Elasmobranchs, polypterids, and many fossil fishes have open spiracles. In Latimeria, most frogs, and all amniotes, a tympanic membrane covering the spiracle evolved independently. The tympanic membrane is displaced by pressure changes and enabled tetrapods to perceive airborne sound pressure waves. The hyomandibular bone is associated with the spiracle/tympanic membrane in actinopterygians and piscine sarcopterygians. In tetrapods, it transforms into the stapes that connects the oval window of the inner ear with the tympanic membrane and allows hearing at higher frequencies by providing an impedance matching and amplification mechanism. The three characters-basilar papilla, cochlear aqueduct, and tympanic membrane-are fluid related elements in sarcopterygians, which interact with a set of unique features in Latimeria. Finally, we explore the possible interaction between the unique intracranial joint, basicranial muscle, and an enlarged notochord that allows fluid flow to the foramen magnum and the cochlear aqueduct which houses a comparatively small brain.
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Affiliation(s)
- Bernd Fritzsch
- Department of Biology & Department of Otolaryngology, University of Iowa, IA, USA
- Correspondence to: Department of Biology & Department of Otolaryngology, University of Iowa, Iowa City, IA, 52242, USA.
| | | | - Karen L. Elliott
- Department of Biology & Department of Otolaryngology, University of Iowa, IA, USA
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14
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Zine A, Fritzsch B. Early Steps towards Hearing: Placodes and Sensory Development. Int J Mol Sci 2023; 24:6994. [PMID: 37108158 PMCID: PMC10139157 DOI: 10.3390/ijms24086994] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2023] [Revised: 04/03/2023] [Accepted: 04/06/2023] [Indexed: 04/29/2023] Open
Abstract
Sensorineural hearing loss is the most prevalent sensory deficit in humans. Most cases of hearing loss are due to the degeneration of key structures of the sensory pathway in the cochlea, such as the sensory hair cells, the primary auditory neurons, and their synaptic connection to the hair cells. Different cell-based strategies to replace damaged inner ear neurosensory tissue aiming at the restoration of regeneration or functional recovery are currently the subject of intensive research. Most of these cell-based treatment approaches require experimental in vitro models that rely on a fine understanding of the earliest morphogenetic steps that underlie the in vivo development of the inner ear since its initial induction from a common otic-epibranchial territory. This knowledge will be applied to various proposed experimental cell replacement strategies to either address the feasibility or identify novel therapeutic options for sensorineural hearing loss. In this review, we describe how ear and epibranchial placode development can be recapitulated by focusing on the cellular transformations that occur as the inner ear is converted from a thickening of the surface ectoderm next to the hindbrain known as the otic placode to an otocyst embedded in the head mesenchyme. Finally, we will highlight otic and epibranchial placode development and morphogenetic events towards progenitors of the inner ear and their neurosensory cell derivatives.
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Affiliation(s)
- Azel Zine
- LBN, Laboratory of Bioengineering and Nanoscience, University of Montpellier, 34193 Montpellier, France
| | - Bernd Fritzsch
- Department of Biology, CLAS, University of Iowa, Iowa City, IA 52242, USA
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15
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Domingo-Muelas A, Duart-Abadia P, Morante-Redolat JM, Jordán-Pla A, Belenguer G, Fabra-Beser J, Paniagua-Herranz L, Pérez-Villalba A, Álvarez-Varela A, Barriga FM, Gil-Sanz C, Ortega F, Batlle E, Fariñas I. Post-transcriptional control of a stemness signature by RNA-binding protein MEX3A regulates murine adult neurogenesis. Nat Commun 2023; 14:373. [PMID: 36690670 PMCID: PMC9871011 DOI: 10.1038/s41467-023-36054-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Accepted: 01/12/2023] [Indexed: 01/25/2023] Open
Abstract
Neural stem cells (NSCs) in the adult murine subependymal zone balance their self-renewal capacity and glial identity with the potential to generate neurons during the lifetime. Adult NSCs exhibit lineage priming via pro-neurogenic fate determinants. However, the protein levels of the neural fate determinants are not sufficient to drive direct differentiation of adult NSCs, which raises the question of how cells along the neurogenic lineage avoid different conflicting fate choices, such as self-renewal and differentiation. Here, we identify RNA-binding protein MEX3A as a post-transcriptional regulator of a set of stemness associated transcripts at critical transitions in the subependymal neurogenic lineage. MEX3A regulates a quiescence-related RNA signature in activated NSCs that is needed for their return to quiescence, playing a role in the long-term maintenance of the NSC pool. Furthermore, it is required for the repression of the same program at the onset of neuronal differentiation. Our data indicate that MEX3A is a pivotal regulator of adult murine neurogenesis acting as a translational remodeller.
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Grants
- EC | EU Framework Programme for Research and Innovation H2020 | H2020 Priority Excellent Science | H2020 European Research Council (H2020 Excellent Science - European Research Council)
- Ministerio de Ciencia e Innovación (MICINN, Spain) - PID2020-119917RB-I00.
- Regional Government of Valencia | Conselleria d'Educació, Investigació, Cultura i Esport (Conselleria d'Educació, Investigació, Cultura i Esport de la Generalitat Valenciana)
- Ministerio de Ciencia e Innovación (MICINN, Spain) - PID2020-117937GB-I00, PID2020-119917RB-I00, PID 2019-109155RB-I00, PID2020-114227RB-I00, RyC-2015-19058, PRE2018-084838. Centro de Investigación Biomédica en Red Enfermedades Neurodegenerativas (CIBERNED, Spain) - MICINN- CB06/05/0086.
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Affiliation(s)
- Ana Domingo-Muelas
- Departamento de Biología Celular, Biología Funcional y Antropología Física, Universidad de Valencia, Valencia, Spain
- Instituto de Biotecnología y Biomedicina (BIOTECMED), Universidad de Valencia, Valencia, Spain
- Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Valencia, Spain
| | - Pere Duart-Abadia
- Departamento de Biología Celular, Biología Funcional y Antropología Física, Universidad de Valencia, Valencia, Spain
- Instituto de Biotecnología y Biomedicina (BIOTECMED), Universidad de Valencia, Valencia, Spain
- Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Valencia, Spain
| | - Jose Manuel Morante-Redolat
- Departamento de Biología Celular, Biología Funcional y Antropología Física, Universidad de Valencia, Valencia, Spain
- Instituto de Biotecnología y Biomedicina (BIOTECMED), Universidad de Valencia, Valencia, Spain
- Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Valencia, Spain
| | - Antonio Jordán-Pla
- Instituto de Biotecnología y Biomedicina (BIOTECMED), Universidad de Valencia, Valencia, Spain
| | - Germán Belenguer
- Departamento de Biología Celular, Biología Funcional y Antropología Física, Universidad de Valencia, Valencia, Spain
- Instituto de Biotecnología y Biomedicina (BIOTECMED), Universidad de Valencia, Valencia, Spain
- Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Valencia, Spain
| | - Jaime Fabra-Beser
- Departamento de Biología Celular, Biología Funcional y Antropología Física, Universidad de Valencia, Valencia, Spain
- Instituto de Biotecnología y Biomedicina (BIOTECMED), Universidad de Valencia, Valencia, Spain
| | - Lucía Paniagua-Herranz
- Departamento de Bioquímica y Biología Molecular, Universidad Complutense de Madrid (UCM), Madrid, Spain
- Instituto Universitario de Investigación en Neuroquímica (IUIN), Madrid, Spain
- Instituto de Investigación Sanitaria San Carlos (IdISSC), Madrid, Spain
| | - Ana Pérez-Villalba
- Departamento de Biología Celular, Biología Funcional y Antropología Física, Universidad de Valencia, Valencia, Spain
- Instituto de Biotecnología y Biomedicina (BIOTECMED), Universidad de Valencia, Valencia, Spain
- Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Valencia, Spain
| | - Adrián Álvarez-Varela
- Institute for Research in Biomedicine (IRB Barcelona), Barcelona, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Barcelona, Spain
| | - Francisco M Barriga
- Institute for Research in Biomedicine (IRB Barcelona), Barcelona, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Barcelona, Spain
| | - Cristina Gil-Sanz
- Departamento de Biología Celular, Biología Funcional y Antropología Física, Universidad de Valencia, Valencia, Spain
- Instituto de Biotecnología y Biomedicina (BIOTECMED), Universidad de Valencia, Valencia, Spain
- Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Valencia, Spain
| | - Felipe Ortega
- Departamento de Bioquímica y Biología Molecular, Universidad Complutense de Madrid (UCM), Madrid, Spain
- Instituto Universitario de Investigación en Neuroquímica (IUIN), Madrid, Spain
- Instituto de Investigación Sanitaria San Carlos (IdISSC), Madrid, Spain
| | - Eduard Batlle
- Institute for Research in Biomedicine (IRB Barcelona), Barcelona, Spain.
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Barcelona, Spain.
- ICREA, Barcelona, Spain.
| | - Isabel Fariñas
- Departamento de Biología Celular, Biología Funcional y Antropología Física, Universidad de Valencia, Valencia, Spain.
- Instituto de Biotecnología y Biomedicina (BIOTECMED), Universidad de Valencia, Valencia, Spain.
- Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Valencia, Spain.
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16
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Domingo-Muelas A, Morante-Redolat JM, Moncho-Amor V, Jordán-Pla A, Pérez-Villalba A, Carrillo-Barberà P, Belenguer G, Porlan E, Kirstein M, Bachs O, Ferrón SR, Lovell-Badge R, Fariñas I. The rates of adult neurogenesis and oligodendrogenesis are linked to cell cycle regulation through p27-dependent gene repression of SOX2. Cell Mol Life Sci 2023; 80:36. [PMID: 36627412 PMCID: PMC9832098 DOI: 10.1007/s00018-022-04676-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2022] [Accepted: 12/15/2022] [Indexed: 01/12/2023]
Abstract
Cell differentiation involves profound changes in global gene expression that often has to occur in coordination with cell cycle exit. Because cyclin-dependent kinase inhibitor p27 reportedly regulates proliferation of neural progenitor cells in the subependymal neurogenic niche of the adult mouse brain, but can also have effects on gene expression, we decided to molecularly analyze its role in adult neurogenesis and oligodendrogenesis. At the cell level, we show that p27 restricts residual cyclin-dependent kinase activity after mitogen withdrawal to antagonize cycling, but it is not essential for cell cycle exit. By integrating genome-wide gene expression and chromatin accessibility data, we find that p27 is coincidentally necessary to repress many genes involved in the transit from multipotentiality to differentiation, including those coding for neural progenitor transcription factors SOX2, OLIG2 and ASCL1. Our data reveal both a direct association of p27 with regulatory sequences in the three genes and an additional hierarchical relationship where p27 repression of Sox2 leads to reduced levels of its downstream targets Olig2 and Ascl1. In vivo, p27 is also required for the regulation of the proper level of SOX2 necessary for neuroblasts and oligodendroglial progenitor cells to timely exit cell cycle in a lineage-dependent manner.
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Affiliation(s)
- Ana Domingo-Muelas
- Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain
- Departamento de Biología Celular Biología Funcional y Antropología Física, Universidad de Valencia, 46100, Burjassot, Spain
- Instituto de Biotecnología y Biomedicina (BioTecMed), Universidad de Valencia, Valencia, Spain
- Department of Cell and Developmental Biology, Smilow Center for Translational Research, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Jose Manuel Morante-Redolat
- Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain
- Departamento de Biología Celular Biología Funcional y Antropología Física, Universidad de Valencia, 46100, Burjassot, Spain
- Instituto de Biotecnología y Biomedicina (BioTecMed), Universidad de Valencia, Valencia, Spain
| | - Verónica Moncho-Amor
- The Francis Crick Institute, London, NW1 1AT, UK
- IIS Biodonostia, 48013, Bilbao, Spain
| | - Antonio Jordán-Pla
- Instituto de Biotecnología y Biomedicina (BioTecMed), Universidad de Valencia, Valencia, Spain
| | - Ana Pérez-Villalba
- Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain
- Departamento de Biología Celular Biología Funcional y Antropología Física, Universidad de Valencia, 46100, Burjassot, Spain
- Instituto de Biotecnología y Biomedicina (BioTecMed), Universidad de Valencia, Valencia, Spain
| | - Pau Carrillo-Barberà
- Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain
- Departamento de Biología Celular Biología Funcional y Antropología Física, Universidad de Valencia, 46100, Burjassot, Spain
- Instituto de Biotecnología y Biomedicina (BioTecMed), Universidad de Valencia, Valencia, Spain
- Institute for Research in Biomedicine, 6500, Bellinzona, Switzerland
| | - Germán Belenguer
- Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain
- Departamento de Biología Celular Biología Funcional y Antropología Física, Universidad de Valencia, 46100, Burjassot, Spain
- Instituto de Biotecnología y Biomedicina (BioTecMed), Universidad de Valencia, Valencia, Spain
- Max Planck Institute of Molecular Cell Biology and Genetics, 01307, Dresden, Germany
| | - Eva Porlan
- Departamento de Biología Molecular, Universidad Autónoma de Madrid (UAM), Madrid, Spain
- Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid (CSIC-UAM), Madrid, Spain
- Instituto de Investigación Hospital Universitario La Paz (IdiPAZ), Instituto de Salud Carlos III, Madrid, Spain
| | - Martina Kirstein
- Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain
- Departamento de Biología Celular Biología Funcional y Antropología Física, Universidad de Valencia, 46100, Burjassot, Spain
- Instituto de Biotecnología y Biomedicina (BioTecMed), Universidad de Valencia, Valencia, Spain
| | - Oriol Bachs
- Department of Biomedical Sciences, University of Barcelona-IDIBAPS, CIBERONC, Barcelona, Spain
| | - Sacri R Ferrón
- Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain
- Departamento de Biología Celular Biología Funcional y Antropología Física, Universidad de Valencia, 46100, Burjassot, Spain
- Instituto de Biotecnología y Biomedicina (BioTecMed), Universidad de Valencia, Valencia, Spain
| | | | - Isabel Fariñas
- Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.
- Departamento de Biología Celular Biología Funcional y Antropología Física, Universidad de Valencia, 46100, Burjassot, Spain.
- Instituto de Biotecnología y Biomedicina (BioTecMed), Universidad de Valencia, Valencia, Spain.
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17
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Stevanovic M, Lazic A, Schwirtlich M, Stanisavljevic Ninkovic D. The Role of SOX Transcription Factors in Ageing and Age-Related Diseases. Int J Mol Sci 2023; 24:851. [PMID: 36614288 PMCID: PMC9821406 DOI: 10.3390/ijms24010851] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Revised: 12/27/2022] [Accepted: 12/28/2022] [Indexed: 01/05/2023] Open
Abstract
The quest for eternal youth and immortality is as old as humankind. Ageing is an inevitable physiological process accompanied by many functional declines that are driving factors for age-related diseases. Stem cell exhaustion is one of the major hallmarks of ageing. The SOX transcription factors play well-known roles in self-renewal and differentiation of both embryonic and adult stem cells. As a consequence of ageing, the repertoire of adult stem cells present in various organs steadily declines, and their dysfunction/death could lead to reduced regenerative potential and development of age-related diseases. Thus, restoring the function of aged stem cells, inducing their regenerative potential, and slowing down the ageing process are critical for improving the health span and, consequently, the lifespan of humans. Reprograming factors, including SOX family members, emerge as crucial players in rejuvenation. This review focuses on the roles of SOX transcription factors in stem cell exhaustion and age-related diseases, including neurodegenerative diseases, visual deterioration, chronic obstructive pulmonary disease, osteoporosis, and age-related cancers. A better understanding of the molecular mechanisms of ageing and the roles of SOX transcription factors in this process could open new avenues for developing novel strategies that will delay ageing and prevent age-related diseases.
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Affiliation(s)
- Milena Stevanovic
- Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Vojvode Stepe 444a, 11042 Belgrade, Serbia
- Faculty of Biology, University of Belgrade, Studentski trg 16, 11158 Belgrade, Serbia
- Serbian Academy of Sciences and Arts, Knez Mihailova 35, 11000 Belgrade, Serbia
| | - Andrijana Lazic
- Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Vojvode Stepe 444a, 11042 Belgrade, Serbia
| | - Marija Schwirtlich
- Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Vojvode Stepe 444a, 11042 Belgrade, Serbia
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18
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Lu J, Xu H, Song K, Lin Z, Cao L, Lu B, Chen Y, Zhang S. Sox11b regulates the migration and fate determination of Müller glia-derived progenitors during retina regeneration in zebrafish. Neural Regen Res 2023; 18:445-450. [PMID: 35900444 PMCID: PMC9396499 DOI: 10.4103/1673-5374.346550] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
The transcription factor Sox11 plays important roles in retinal neurogenesis during vertebrate eye development. However, its function in retina regeneration remains elusive. Here we report that Sox11b, a zebrafish Sox11 homolog, regulates the migration and fate determination of Müller glia-derived progenitors (MGPCs) in an adult zebrafish model of mechanical retinal injury. Following a stab injury, the expression of Sox11b was induced in proliferating MGPCs in the retina. Sox11b knockdown did not affect MGPC formation at 4 days post-injury, although the nuclear morphology and subsequent radial migration of MGPCs were altered. At 7 days post-injury, Sox11b knockdown resulted in an increased proportion of MGPCs in the inner retina and a decreased proportion of MGPCs in the outer nuclear layer, compared with controls. Furthermore, Sox11b knockdown led to reduced photoreceptor regeneration, while it increased the numbers of newborn amacrines and retinal ganglion cells. Finally, quantitative polymerase chain reaction analysis revealed that Sox11b regulated the expression of Notch signaling components in the retina, and Notch inhibition partially recapitulated the Sox11b knockdown phenotype, indicating that Notch signaling functions downstream of Sox11b. Our findings imply that Sox11b plays key roles in MGPC migration and fate determination during retina regeneration in zebrafish, which may have critical implications for future explorations of retinal repair in mammals.
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19
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Fritzsch B, Elliott KL, Yamoah EN. Neurosensory development of the four brainstem-projecting sensory systems and their integration in the telencephalon. Front Neural Circuits 2022; 16:913480. [PMID: 36213204 PMCID: PMC9539932 DOI: 10.3389/fncir.2022.913480] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2022] [Accepted: 08/23/2022] [Indexed: 11/18/2022] Open
Abstract
Somatosensory, taste, vestibular, and auditory information is first processed in the brainstem. From the brainstem, the respective information is relayed to specific regions within the cortex, where these inputs are further processed and integrated with other sensory systems to provide a comprehensive sensory experience. We provide the organization, genetics, and various neuronal connections of four sensory systems: trigeminal, taste, vestibular, and auditory systems. The development of trigeminal fibers is comparable to many sensory systems, for they project mostly contralaterally from the brainstem or spinal cord to the telencephalon. Taste bud information is primarily projected ipsilaterally through the thalamus to reach the insula. The vestibular fibers develop bilateral connections that eventually reach multiple areas of the cortex to provide a complex map. The auditory fibers project in a tonotopic contour to the auditory cortex. The spatial and tonotopic organization of trigeminal and auditory neuron projections are distinct from the taste and vestibular systems. The individual sensory projections within the cortex provide multi-sensory integration in the telencephalon that depends on context-dependent tertiary connections to integrate other cortical sensory systems across the four modalities.
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Affiliation(s)
- Bernd Fritzsch
- Department of Biology, The University of Iowa, Iowa City, IA, United States
- Department of Otolaryngology, The University of Iowa, Iowa City, IA, United States
- *Correspondence: Bernd Fritzsch,
| | - Karen L. Elliott
- Department of Biology, The University of Iowa, Iowa City, IA, United States
| | - Ebenezer N. Yamoah
- Department of Physiology and Cell Biology, School of Medicine, University of Nevada, Reno, Reno, NV, United States
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20
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Comparative role of SOX10 gene in the gliogenesis of central, peripheral, and enteric nervous systems. Differentiation 2022; 128:13-25. [DOI: 10.1016/j.diff.2022.09.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2022] [Revised: 09/10/2022] [Accepted: 09/19/2022] [Indexed: 11/17/2022]
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21
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Mora A, Rakar J, Cobeta IM, Salmani BY, Starkenberg A, Thor S, Bodén M. Variational autoencoding of gene landscapes during mouse CNS development uncovers layered roles of Polycomb Repressor Complex 2. Nucleic Acids Res 2022; 50:1280-1296. [PMID: 35048973 PMCID: PMC8860581 DOI: 10.1093/nar/gkac006] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Revised: 12/22/2021] [Accepted: 01/05/2022] [Indexed: 12/13/2022] Open
Abstract
A prominent aspect of most, if not all, central nervous systems (CNSs) is that anterior regions (brain) are larger than posterior ones (spinal cord). Studies in Drosophila and mouse have revealed that Polycomb Repressor Complex 2 (PRC2), a protein complex responsible for applying key repressive histone modifications, acts by several mechanisms to promote anterior CNS expansion. However, it is unclear what the full spectrum of PRC2 action is during embryonic CNS development and how PRC2 intersects with the epigenetic landscape. We removed PRC2 function from the developing mouse CNS, by mutating the key gene Eed, and generated spatio-temporal transcriptomic data. To decode the role of PRC2, we developed a method that incorporates standard statistical analyses with probabilistic deep learning to integrate the transcriptomic response to PRC2 inactivation with epigenetic data. This multi-variate analysis corroborates the central involvement of PRC2 in anterior CNS expansion, and also identifies several unanticipated cohorts of genes, such as proliferation and immune response genes. Furthermore, the analysis reveals specific profiles of regulation via PRC2 upon these gene cohorts. These findings uncover a differential logic for the role of PRC2 upon functionally distinct gene cohorts that drive CNS anterior expansion. To support the analysis of emerging multi-modal datasets, we provide a novel bioinformatics package that integrates transcriptomic and epigenetic datasets to identify regulatory underpinnings of heterogeneous biological processes.
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Affiliation(s)
- Ariane Mora
- School of Chemistry and Molecular Biosciences, University of Queensland, St Lucia, QLD 4072, Australia
| | - Jonathan Rakar
- Department of Clinical and Experimental Medicine, Linköping University, SE-58185 Linköping, Sweden
| | - Ignacio Monedero Cobeta
- Department of Clinical and Experimental Medicine, Linköping University, SE-58185 Linköping, Sweden
- Department of Physiology, Universidad Autonoma de Madrid, Madrid, Spain
| | - Behzad Yaghmaeian Salmani
- Department of Clinical and Experimental Medicine, Linköping University, SE-58185 Linköping, Sweden
- Department of Cell and Molecular Biology, Karolinska Institute, SE-171 65 Stockholm, Sweden
| | - Annika Starkenberg
- Department of Clinical and Experimental Medicine, Linköping University, SE-58185 Linköping, Sweden
| | - Stefan Thor
- Department of Clinical and Experimental Medicine, Linköping University, SE-58185 Linköping, Sweden
- School of Biomedical Sciences, University of Queensland, St Lucia, QLD 4072, Australia
| | - Mikael Bodén
- School of Chemistry and Molecular Biosciences, University of Queensland, St Lucia, QLD 4072, Australia
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22
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Boesmans W, Nash A, Tasnády KR, Yang W, Stamp LA, Hao MM. Development, Diversity, and Neurogenic Capacity of Enteric Glia. Front Cell Dev Biol 2022; 9:775102. [PMID: 35111752 PMCID: PMC8801887 DOI: 10.3389/fcell.2021.775102] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Accepted: 12/09/2021] [Indexed: 12/15/2022] Open
Abstract
Enteric glia are a fascinating population of cells. Initially identified in the gut wall as the "support" cells of the enteric nervous system, studies over the past 20 years have unveiled a vast array of functions carried out by enteric glia. They mediate enteric nervous system signalling and play a vital role in the local regulation of gut functions. Enteric glial cells interact with other gastrointestinal cell types such as those of the epithelium and immune system to preserve homeostasis, and are perceptive to luminal content. Their functional versatility and phenotypic heterogeneity are mirrored by an extensive level of plasticity, illustrated by their reactivity in conditions associated with enteric nervous system dysfunction and disease. As one of the hallmarks of their plasticity and extending their operative relationship with enteric neurons, enteric glia also display neurogenic potential. In this review, we focus on the development of enteric glial cells, and the mechanisms behind their heterogeneity in the adult gut. In addition, we discuss what is currently known about the role of enteric glia as neural precursors in the enteric nervous system.
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Affiliation(s)
- Werend Boesmans
- Biomedical Research Institute (BIOMED), Hasselt University, Hasselt, Belgium
- Department of Pathology, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Centre, Maastricht, Netherlands
| | - Amelia Nash
- Department of Anatomy and Physiology, The University of Melbourne, Melbourne, VIC, Australia
| | - Kinga R. Tasnády
- Biomedical Research Institute (BIOMED), Hasselt University, Hasselt, Belgium
- Department of Pathology, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Centre, Maastricht, Netherlands
| | - Wendy Yang
- Department of Anatomy and Physiology, The University of Melbourne, Melbourne, VIC, Australia
- Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taiwan, Taiwan
| | - Lincon A. Stamp
- Department of Anatomy and Physiology, The University of Melbourne, Melbourne, VIC, Australia
| | - Marlene M. Hao
- Department of Anatomy and Physiology, The University of Melbourne, Melbourne, VIC, Australia
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23
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Stevanovic M, Kovacevic-Grujicic N, Mojsin M, Milivojevic M, Drakulic D. SOX transcription factors and glioma stem cells: Choosing between stemness and differentiation. World J Stem Cells 2021; 13:1417-1445. [PMID: 34786152 PMCID: PMC8567447 DOI: 10.4252/wjsc.v13.i10.1417] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Revised: 07/15/2021] [Accepted: 09/16/2021] [Indexed: 02/06/2023] Open
Abstract
Glioblastoma (GBM) is the most common, most aggressive and deadliest brain tumor. Recently, remarkable progress has been made towards understanding the cellular and molecular biology of gliomas. GBM tumor initiation, progression and relapse as well as resistance to treatments are associated with glioma stem cells (GSCs). GSCs exhibit a high proliferation rate and self-renewal capacity and the ability to differentiate into diverse cell types, generating a range of distinct cell types within the tumor, leading to cellular heterogeneity. GBM tumors may contain different subsets of GSCs, and some of them may adopt a quiescent state that protects them against chemotherapy and radiotherapy. GSCs enriched in recurrent gliomas acquire more aggressive and therapy-resistant properties, making them more malignant, able to rapidly spread. The impact of SOX transcription factors (TFs) on brain tumors has been extensively studied in the last decade. Almost all SOX genes are expressed in GBM, and their expression levels are associated with patient prognosis and survival. Numerous SOX TFs are involved in the maintenance of the stemness of GSCs or play a role in the initiation of GSC differentiation. The fine-tuning of SOX gene expression levels controls the balance between cell stemness and differentiation. Therefore, innovative therapies targeting SOX TFs are emerging as promising tools for combatting GBM. Combatting GBM has been a demanding and challenging goal for decades. The current therapeutic strategies have not yet provided a cure for GBM and have only resulted in a slight improvement in patient survival. Novel approaches will require the fine adjustment of multimodal therapeutic strategies that simultaneously target numerous hallmarks of cancer cells to win the battle against GBM.
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Affiliation(s)
- Milena Stevanovic
- Laboratory for Human Molecular Genetics, Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Belgrade 11042, Serbia
- Chair Biochemistry and Molecular Biology, Faculty of Biology, University of Belgrade, Belgrade 11158, Serbia
- Department of Chemical and Biological Sciences, Serbian Academy of Sciences and Arts, Belgrade 11000, Serbia.
| | - Natasa Kovacevic-Grujicic
- Laboratory for Human Molecular Genetics, Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Belgrade 11042, Serbia
| | - Marija Mojsin
- Laboratory for Human Molecular Genetics, Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Belgrade 11042, Serbia
| | - Milena Milivojevic
- Laboratory for Human Molecular Genetics, Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Belgrade 11042, Serbia
| | - Danijela Drakulic
- Laboratory for Human Molecular Genetics, Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Belgrade 11042, Serbia
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24
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Fritzsch B. An Integrated Perspective of Evolution and Development: From Genes to Function to Ear, Lateral Line and Electroreception. DIVERSITY 2021; 13:364. [PMID: 35505776 PMCID: PMC9060560 DOI: 10.3390/d13080364] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Four sensory systems (vestibular, lateral line, electroreception, auditory) are unique and project exclusively to the brainstem of vertebrates. All sensory neurons depend on a common set of genes (Eya1, Sox2, Neurog1, Neurod1) that project to a dorsal nucleus and an intermediate nucleus, which differentiate into the vestibular ear, lateral line and electroreception in vertebrates. In tetrapods, a loss of two sensory systems (lateral line, electroreception) leads to the development of a unique ear and auditory system in amniotes. Lmx1a/b, Gdf7, Wnt1/3a, BMP4/7 and Atoh1 define the lateral line, electroreception and auditory nuclei. In contrast, vestibular nuclei depend on Neurog1/2, Ascl1, Ptf1a and Olig3, among others, to develop an independent origin of the vestibular nuclei. A common origin of hair cells depends on Eya1, Sox2 and Atoh1, which generate the mechanosensory cells. Several proteins define the polarity of hair cells in the ear and lateral line. A unique connection of stereocilia requires CDH23 and PCDH15 for connections and TMC1/2 proteins to perceive mechanosensory input. Electroreception has no polarity, and a different system is used to drive electroreceptors. All hair cells function by excitation via ribbons to activate neurons that innervate the distinct target areas. An integrated perspective is presented to understand the gain and loss of different sensory systems.
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Affiliation(s)
- Bernd Fritzsch
- Department of Biology & Department of Otolaryngology, University of Iowa, Iowa City, IA 52242, USA
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25
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Wittmann MT, Katada S, Sock E, Kirchner P, Ekici AB, Wegner M, Nakashima K, Lie DC, Reis A. scRNA sequencing uncovers a TCF4-dependent transcription factor network regulating commissure development in mouse. Development 2021; 148:269257. [PMID: 34184026 PMCID: PMC8327186 DOI: 10.1242/dev.196022] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2020] [Accepted: 06/15/2021] [Indexed: 01/21/2023]
Abstract
Transcription factor 4 (TCF4) is a crucial regulator of neurodevelopment and has been linked to the pathogenesis of autism, intellectual disability and schizophrenia. As a class I bHLH transcription factor (TF), it is assumed that TCF4 exerts its neurodevelopmental functions through dimerization with proneural class II bHLH TFs. Here, we aim to identify TF partners of TCF4 in the control of interhemispheric connectivity formation. Using a new bioinformatic strategy integrating TF expression levels and regulon activities from single cell RNA-sequencing data, we find evidence that TCF4 interacts with non-bHLH TFs and modulates their transcriptional activity in Satb2+ intercortical projection neurons. Notably, this network comprises regulators linked to the pathogenesis of neurodevelopmental disorders, e.g. FOXG1, SOX11 and BRG1. In support of the functional interaction of TCF4 with non-bHLH TFs, we find that TCF4 and SOX11 biochemically interact and cooperatively control commissure formation in vivo, and regulate the transcription of genes implicated in this process. In addition to identifying new candidate interactors of TCF4 in neurodevelopment, this study illustrates how scRNA-Seq data can be leveraged to predict TF networks in neurodevelopmental processes. Summary: Single-cell RNA sequencing identifies interactions of TCF4 with non-bHLH transcription factors linked to neurodevelopmental and neuropsychiatric disease in the regulation of interhemispheric projection neuron development.
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Affiliation(s)
- Marie-Theres Wittmann
- Institute of Human Genetics, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany.,Institute of Biochemistry, Emil Fischer Center, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany
| | - Sayako Katada
- Department of Stem Cell Biology and Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
| | - Elisabeth Sock
- Institute of Biochemistry, Emil Fischer Center, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany
| | - Philipp Kirchner
- Institute of Human Genetics, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany
| | - Arif B Ekici
- Institute of Human Genetics, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany
| | - Michael Wegner
- Institute of Biochemistry, Emil Fischer Center, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany
| | - Kinichi Nakashima
- Department of Stem Cell Biology and Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
| | - Dieter Chichung Lie
- Institute of Biochemistry, Emil Fischer Center, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany
| | - André Reis
- Institute of Human Genetics, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany
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26
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Stevanovic M, Drakulic D, Lazic A, Ninkovic DS, Schwirtlich M, Mojsin M. SOX Transcription Factors as Important Regulators of Neuronal and Glial Differentiation During Nervous System Development and Adult Neurogenesis. Front Mol Neurosci 2021; 14:654031. [PMID: 33867936 PMCID: PMC8044450 DOI: 10.3389/fnmol.2021.654031] [Citation(s) in RCA: 78] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2021] [Accepted: 03/11/2021] [Indexed: 12/11/2022] Open
Abstract
The SOX proteins belong to the superfamily of transcription factors (TFs) that display properties of both classical TFs and architectural components of chromatin. Since the cloning of the Sox/SOX genes, remarkable progress has been made in illuminating their roles as key players in the regulation of multiple developmental and physiological processes. SOX TFs govern diverse cellular processes during development, such as maintaining the pluripotency of stem cells, cell proliferation, cell fate decisions/germ layer formation as well as terminal cell differentiation into tissues and organs. However, their roles are not limited to development since SOX proteins influence survival, regeneration, cell death and control homeostasis in adult tissues. This review summarized current knowledge of the roles of SOX proteins in control of central nervous system development. Some SOX TFs suspend neural progenitors in proliferative, stem-like state and prevent their differentiation. SOX proteins function as pioneer factors that occupy silenced target genes and keep them in a poised state for activation at subsequent stages of differentiation. At appropriate stage of development, SOX members that maintain stemness are down-regulated in cells that are competent to differentiate, while other SOX members take over their functions and govern the process of differentiation. Distinct SOX members determine down-stream processes of neuronal and glial differentiation. Thus, sequentially acting SOX TFs orchestrate neural lineage development defining neuronal and glial phenotypes. In line with their crucial roles in the nervous system development, deregulation of specific SOX proteins activities is associated with neurodevelopmental disorders (NDDs). The overview of the current knowledge about the link between SOX gene variants and NDDs is presented. We outline the roles of SOX TFs in adult neurogenesis and brain homeostasis and discuss whether impaired adult neurogenesis, detected in neurodegenerative diseases, could be associated with deregulation of SOX proteins activities. We present the current data regarding the interaction between SOX proteins and signaling pathways and microRNAs that play roles in nervous system development. Finally, future research directions that will improve the knowledge about distinct and various roles of SOX TFs in health and diseases are presented and discussed.
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Affiliation(s)
- Milena Stevanovic
- Laboratory for Human Molecular Genetics, Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Belgrade, Serbia.,Faculty of Biology, University of Belgrade, Belgrade, Serbia.,Serbian Academy of Sciences and Arts, Belgrade, Serbia
| | - Danijela Drakulic
- Laboratory for Human Molecular Genetics, Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Belgrade, Serbia
| | - Andrijana Lazic
- Laboratory for Human Molecular Genetics, Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Belgrade, Serbia
| | - Danijela Stanisavljevic Ninkovic
- Laboratory for Human Molecular Genetics, Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Belgrade, Serbia
| | - Marija Schwirtlich
- Laboratory for Human Molecular Genetics, Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Belgrade, Serbia
| | - Marija Mojsin
- Laboratory for Human Molecular Genetics, Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Belgrade, Serbia
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27
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Chiang SY, Wu HC, Lin SY, Chen HY, Wang CF, Yeh NH, Shih JH, Huang YS, Kuo HC, Chou SJ, Chen RH. Usp11 controls cortical neurogenesis and neuronal migration through Sox11 stabilization. SCIENCE ADVANCES 2021; 7:7/7/eabc6093. [PMID: 33579706 PMCID: PMC7880594 DOI: 10.1126/sciadv.abc6093] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/04/2020] [Accepted: 12/23/2020] [Indexed: 06/01/2023]
Abstract
The role of protein stabilization in cortical development remains poorly understood. A recessive mutation in the USP11 gene is found in a rare neurodevelopmental disorder with intellectual disability, but its pathogenicity and molecular mechanism are unknown. Here, we show that mouse Usp11 is expressed highly in embryonic cerebral cortex, and Usp11 deficiency impairs layer 6 neuron production, delays late-born neuronal migration, and disturbs cognition and anxiety behaviors. Mechanistically, these functions are mediated by a previously unidentified Usp11 substrate, Sox11. Usp11 ablation compromises Sox11 protein accumulation in the developing cortex, despite the induction of Sox11 mRNA. The disease-associated Usp11 mutant fails to stabilize Sox11 and is unable to support cortical neurogenesis and neuronal migration. Our findings define a critical function of Usp11 in cortical development and highlight the importance of orchestrating protein stabilization mechanisms into transcription regulatory programs for a robust induction of cell fate determinants during early brain development.
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Affiliation(s)
- Shang-Yin Chiang
- Institute of Biological Chemistry, Academia Sinica, Taipei 115, Taiwan
- Institute of Biochemical Sciences, College of Life Science, National Taiwan University, Taipei 100, Taiwan
| | - Hsin-Chieh Wu
- Institute of Biological Chemistry, Academia Sinica, Taipei 115, Taiwan
| | - Shu-Yu Lin
- Institute of Biological Chemistry, Academia Sinica, Taipei 115, Taiwan
| | - Hsin-Yi Chen
- Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 110, Taiwan
| | - Chia-Fang Wang
- Institute of Cellular and Organismic Biology, Academia Sinica, Taipei 115, Taiwan
| | - Nai-Hsing Yeh
- Insititute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan
| | - Jou-Ho Shih
- Insititute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan
| | - Yi-Shuian Huang
- Insititute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan
| | - Hung-Chih Kuo
- Institute of Cellular and Organismic Biology, Academia Sinica, Taipei 115, Taiwan
| | - Shen-Ju Chou
- Institute of Cellular and Organismic Biology, Academia Sinica, Taipei 115, Taiwan.
| | - Ruey-Hwa Chen
- Institute of Biological Chemistry, Academia Sinica, Taipei 115, Taiwan.
- Institute of Biochemical Sciences, College of Life Science, National Taiwan University, Taipei 100, Taiwan
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28
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Yao C, Wan H, Zhang Z, Lin J, Wang Y. Genome-wide identification and expression profile of the sox gene family in different tissues and during embryogenesis in the Pacific white shrimp (Litopenaeus vannamei). Gene 2020; 763:144956. [DOI: 10.1016/j.gene.2020.144956] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2020] [Revised: 06/22/2020] [Accepted: 07/13/2020] [Indexed: 02/06/2023]
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29
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McAninch D, Thomson EP, Thomas PQ. Genome-wide DNA-binding profile of SRY-box transcription factor 3 (SOX3) in mouse testes. Reprod Fertil Dev 2020; 32:1260-1270. [PMID: 33166488 DOI: 10.1071/rd20108] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2020] [Accepted: 10/01/2020] [Indexed: 12/14/2022] Open
Abstract
Spermatogenesis is the male version of gametogenesis, where germ cells are transformed into haploid spermatozoa through a tightly controlled series of mitosis, meiosis and differentiation. This process is reliant on precisely timed changes in gene expression controlled by several different hormonal and transcriptional mechanisms. One important transcription factor is SRY-box transcription factor 3 (SOX3), which is transiently expressed within the uncommitted spermatogonial stem cell population. Sox3-null mouse testes exhibit a block in spermatogenesis, leading to infertility or subfertility. However, the molecular role of SOX3 during spermatogonial differentiation remains poorly understood because the genomic regions targeted by this transcription factor have not been identified. In this study we used chromatin immunoprecipitation sequencing to identify and characterise the endogenous genome-wide binding profile of SOX3 in mouse testes at Postnatal Day 7. We show that neurogenin3 (Neurog3 or Ngn3) is directly targeted by SOX3 in spermatogonial stem cells via a novel testes-specific binding site. We also implicate SOX3, for the first time, in direct regulation of histone gene expression and demonstrate that this function is shared by both neural progenitors and testes, and with another important transcription factor required for spermatogenesis, namely promyelocytic leukaemia zinc-finger (PLZF). Together, these data provide new insights into the function of SOX3 in different stem cell contexts.
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Affiliation(s)
- Dale McAninch
- School of Biological Sciences and Robinson Research Institute, University of Adelaide, North Terrace, Adelaide, SA 5005, Australia
| | - Ella P Thomson
- School of Biological Sciences and Robinson Research Institute, University of Adelaide, North Terrace, Adelaide, SA 5005, Australia
| | - Paul Q Thomas
- School of Biological Sciences and Robinson Research Institute, University of Adelaide, North Terrace, Adelaide, SA 5005, Australia; and Adelaide Medical School, University of Adelaide, North Terrace, Adelaide, SA 5005, Australia; and Precision Medicine Theme, South Australia Health and Medical Research Institute, North Terrace, Adelaide, SA 5000, Australia; and Corresponding author.
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30
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Arefin B, Parvin F, Bahrampour S, Stadler CB, Thor S. Drosophila Neuroblast Selection Is Gated by Notch, Snail, SoxB, and EMT Gene Interplay. Cell Rep 2020; 29:3636-3651.e3. [PMID: 31825841 DOI: 10.1016/j.celrep.2019.11.038] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2019] [Revised: 10/20/2019] [Accepted: 11/08/2019] [Indexed: 12/14/2022] Open
Abstract
In the developing Drosophila central nervous system (CNS), neural progenitor (neuroblast [NB]) selection is gated by lateral inhibition, controlled by Notch signaling and proneural genes. However, proneural mutants still generate many NBs, indicating the existence of additional proneural genes. Moreover, recent studies reveal involvement of key epithelial-mesenchymal transition (EMT) genes in NB selection, but the regulatory interplay between Notch signaling and the EMT machinery is unclear. We find that SoxNeuro (SoxB family) and worniu (Snail family) are integrated with the Notch pathway, and constitute the missing proneural genes. Notch signaling, the proneural, SoxNeuro, and worniu genes regulate key EMT genes to orchestrate the NB selection process. Hence, we uncover an expanded lateral inhibition network for NB selection and demonstrate its link to key players in the EMT machinery. The evolutionary conservation of the genes involved suggests that the Notch-SoxB-Snail-EMT network may control neural progenitor selection in many other systems.
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Affiliation(s)
- Badrul Arefin
- Department of Clinical and Experimental Medicine, Linkoping University, 58185 Linkoping, Sweden
| | - Farjana Parvin
- Department of Clinical and Experimental Medicine, Linkoping University, 58185 Linkoping, Sweden
| | - Shahrzad Bahrampour
- Department of Clinical and Experimental Medicine, Linkoping University, 58185 Linkoping, Sweden
| | - Caroline Bivik Stadler
- Department of Clinical and Experimental Medicine, Linkoping University, 58185 Linkoping, Sweden
| | - Stefan Thor
- Department of Clinical and Experimental Medicine, Linkoping University, 58185 Linkoping, Sweden; School of Biomedical Sciences, University of Queensland, St. Lucia, QLD 4072, Australia.
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SOX3 promotes generation of committed spermatogonia in postnatal mouse testes. Sci Rep 2020; 10:6751. [PMID: 32317665 PMCID: PMC7174399 DOI: 10.1038/s41598-020-63290-3] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2017] [Accepted: 03/19/2020] [Indexed: 01/19/2023] Open
Abstract
SOX3 is a transcription factor expressed within the developing and adult nervous system where it mostly functions to help maintain neural precursors. Sox3 is also expressed in other locations, notably within the spermatogonial stem/progenitor cell population in postnatal testis. Independent studies have shown that Sox3 null mice exhibit a spermatogenic block as young adults, the mechanism of which remains poorly understood. Using a panel of spermatogonial cell marker genes, we demonstrate that Sox3 is expressed within the committed progenitor fraction of the undifferentiated spermatogonial pool. Additionally, we use a Sox3 null mouse model to define a potential role for this factor in progenitor cell function. We demonstrate that Sox3 expression is required for transition of undifferentiated cells from a GFRα1+ self-renewing state to the NGN3 + transit-amplifying compartment. Critically, using chromatin immunoprecipitation, we demonstrate that SOX3 binds to a highly conserved region in the Ngn3 promoter region in vivo, indicating that Ngn3 is a direct target of SOX3. Together these studies indicate that SOX3 functions as a pro-commitment factor in spermatogonial stem/progenitor cells.
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32
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Dvorakova M, Macova I, Bohuslavova R, Anderova M, Fritzsch B, Pavlinkova G. Early ear neuronal development, but not olfactory or lens development, can proceed without SOX2. Dev Biol 2020; 457:43-56. [PMID: 31526806 PMCID: PMC6938654 DOI: 10.1016/j.ydbio.2019.09.003] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2019] [Revised: 09/12/2019] [Accepted: 09/13/2019] [Indexed: 12/25/2022]
Abstract
SOX2 is essential for maintaining neurosensory stem cell properties, although its involvement in the early neurosensory development of cranial placodes remains unclear. To address this, we used Foxg1-Cre to conditionally delete Sox2 during eye, ear, and olfactory placode development. Foxg1-Cre mediated early deletion of Sox2 eradicates all olfactory placode development, and disrupts retinal development and invagination of the lens placode. In contrast to the lens and olfactory placodes, the ear placode invaginates and delaminates NEUROD1 positive neurons. Furthermore, we show that SOX2 is not necessary for early ear neurogenesis, since the early inner ear ganglion is formed with near normal central projections to the hindbrain and peripheral projections to the undifferentiated sensory epithelia of E11.5-12.5 ears. However, later stages of ear neurosensory development, in particular, the late forming auditory system, critically depend on the presence of SOX2. Our data establish distinct differences for SOX2 requirements among placodal sensory organs with similarities between olfactory and lens but not ear placode development, consistent with the unique neurosensory development and molecular properties of the ear.
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Affiliation(s)
| | - Iva Macova
- Institute of Biotechnology CAS, Vestec, Czechia
| | | | | | - Bernd Fritzsch
- Department of Biology, University of Iowa, Iowa City, IA, USA.
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Haseeb A, Lefebvre V. The SOXE transcription factors-SOX8, SOX9 and SOX10-share a bi-partite transactivation mechanism. Nucleic Acids Res 2019; 47:6917-6931. [PMID: 31194875 PMCID: PMC6649842 DOI: 10.1093/nar/gkz523] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2019] [Revised: 05/23/2019] [Accepted: 06/03/2019] [Indexed: 12/20/2022] Open
Abstract
SOX8, SOX9 and SOX10 compose the SOXE transcription factor group. They govern cell fate and differentiation in many lineages, and mutations impairing their activity cause severe diseases, including campomelic dysplasia (SOX9), sex determination disorders (SOX8 and SOX9) and Waardenburg-Shah syndrome (SOX10). However, incomplete knowledge of their modes of action limits disease understanding. We here uncover that the proteins share a bipartite transactivation mechanism, whereby a transactivation domain in the middle of the proteins (TAM) synergizes with a C-terminal one (TAC). TAM comprises amphipathic α-helices predicted to form a protein-binding pocket and overlapping with minimal transactivation motifs (9-aa-TAD) described in many transcription factors. One 9-aa-TAD sequence includes an evolutionarily conserved and functionally required EΦ[D/E]QYΦ motif. SOXF proteins (SOX7, SOX17 and SOX18) contain an identical motif, suggesting evolution from a common ancestor already harboring this motif, whereas TAC and other transactivating SOX proteins feature only remotely related motifs. Missense variants in this SOXE/SOXF-specific motif are rare in control individuals, but have been detected in cancers, supporting its importance in development and physiology. By deepening understanding of mechanisms underlying the central transactivation function of SOXE proteins, these findings should help further decipher molecular networks essential for development and health and dysregulated in diseases.
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Affiliation(s)
- Abdul Haseeb
- Department of Surgery/Division of Orthopaedic Surgery, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA
| | - Véronique Lefebvre
- Department of Surgery/Division of Orthopaedic Surgery, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA
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Crazy Little Thing Called Sox-New Insights in Oligodendroglial Sox Protein Function. Int J Mol Sci 2019; 20:ijms20112713. [PMID: 31159496 PMCID: PMC6600536 DOI: 10.3390/ijms20112713] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2019] [Revised: 05/29/2019] [Accepted: 05/30/2019] [Indexed: 02/06/2023] Open
Abstract
In the central nervous system, oligodendrocytes wrap axons with myelin sheaths, which is essential for rapid transfer of electric signals and their trophic support. In oligodendroglia, transcription factors of the Sox protein family are pivotal regulators of a variety of developmental processes. These include specification, proliferation, and migration of oligodendrocyte precursor cells as well as terminal differentiation to mature myelinating oligodendrocytes. Sox proteins are further affected in demyelinating diseases and are involved in remyelination following damage of the central nervous system. Here we summarize and discuss latest findings on transcriptional regulation of Sox proteins, their function, target genes, and interaction with other transcription factors and chromatin remodelers in oligodendroglia with physiological and pathophysiological relevance.
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Fritzsch B, Elliott KL, Pavlinkova G, Duncan JS, Hansen MR, Kersigo JM. Neuronal Migration Generates New Populations of Neurons That Develop Unique Connections, Physiological Properties and Pathologies. Front Cell Dev Biol 2019; 7:59. [PMID: 31069224 PMCID: PMC6491807 DOI: 10.3389/fcell.2019.00059] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2019] [Accepted: 04/04/2019] [Indexed: 12/16/2022] Open
Abstract
Central nervous system neurons become postmitotic when radial glia cells divide to form neuroblasts. Neuroblasts may migrate away from the ventricle radially along glia fibers, in various directions or even across the midline. We present four cases of unusual migration that are variably connected to either pathology or formation of new populations of neurons with new connectivities. One of the best-known cases of radial migration involves granule cells that migrate from the external granule cell layer along radial Bergman glia fibers to become mature internal granule cells. In various medulloblastoma cases this migration does not occur and transforms the external granule cell layer into a rapidly growing tumor. Among the ocular motor neurons is one unique population that undergoes a contralateral migration and uniquely innervates the superior rectus and levator palpebrae muscles. In humans, a mutation of a single gene ubiquitously expressed in all cells, induces innervation defects only in this unique motor neuron population, leading to inability to elevate eyes or upper eyelids. One of the best-known cases for longitudinal migration is the facial branchial motor (FBM) neurons and the overlapping inner ear efferent population. We describe here molecular cues that are needed for the caudal migration of FBM to segregate these motor neurons from the differently migrating inner ear efferent population. Finally, we describe unusual migration of inner ear spiral ganglion neurons that result in aberrant connections with disruption of frequency presentation. Combined, these data identify unique migratory properties of various neuronal populations that allow them to adopt new connections but also sets them up for unique pathologies.
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Affiliation(s)
- Bernd Fritzsch
- Department of Biology, University of Iowa, Iowa City, IA, United States.,Department of Otolaryngology, University of Iowa, Iowa City, IA, United States
| | - Karen L Elliott
- Department of Biology, University of Iowa, Iowa City, IA, United States
| | | | - Jeremy S Duncan
- Department of Biological Sciences, Western Michigan University, Kalamazoo, MI, United States
| | - Marlan R Hansen
- Department of Otolaryngology, University of Iowa, Iowa City, IA, United States
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Bahrampour S, Jonsson C, Thor S. Brain expansion promoted by polycomb-mediated anterior enhancement of a neural stem cell proliferation program. PLoS Biol 2019; 17:e3000163. [PMID: 30807568 PMCID: PMC6407790 DOI: 10.1371/journal.pbio.3000163] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2018] [Revised: 03/08/2019] [Accepted: 02/08/2019] [Indexed: 12/31/2022] Open
Abstract
During central nervous system (CNS) development, genetic programs establish neural stem cells and drive both stem and daughter cell proliferation. However, the prominent anterior expansion of the CNS implies anterior–posterior (A–P) modulation of these programs. In Drosophila, a set of neural stem cell factors acts along the entire A–P axis to establish neural stem cells. Brain expansion results from enhanced stem and daughter cell proliferation, promoted by a Polycomb Group (PcG)->Homeobox (Hox) homeotic network. But how does PcG->Hox modulate neural-stem-cell–factor activity along the A–P axis? We find that the PcG->Hox network creates an A–P expression gradient of neural stem cell factors, thereby driving a gradient of proliferation. PcG mutants can be rescued by misexpression of the neural stem cell factors or by mutation of one single Hox gene. Hence, brain expansion results from anterior enhancement of core neural-stem-cell–factor expression, mediated by PcG repression of brain Hox expression. A study in fruit flies shows that the anterior expansion of the central nervous system, to form the brain, is driven by Polycomb-mediated repression of Hox genes, resulting in anterior enhancement of a neural stem cell program. The central nervous system displays a pronounced anterior expansion that forms the brain. In the fruit fly Drosophila melanogaster, this expansion is driven by enhanced anterior cell proliferation. Recent studies reveal that cell proliferation in the brain is promoted by the Polycomb Group Complex, a key epigenetic complex. During development of the central nervous system, the Polycomb Group Complex acts to exclude Hox homeotic gene expression from the brain, thereby rendering the brain a Hox-free zone. Hox genes act in an antiproliferative manner, which explains the hyperproliferation observed in the brain, as well as the gradient of proliferation along the anterior–posterior axis of the central nervous system. Here, we find that Hox genes act by repressing a common neural stem cell proliferation program in more posterior regions, resulting in an anterior–posterior gradient of “stemness.” Hence, elevated anterior proliferation is promoted by the Polycomb Group Complex acting to keep the brain free of negative Hox input, thereby ensuring elevated expression of neural stem cell factors in the brain. Strikingly, mutants of the Polycomb Group Complex can be rescued by mutation of one single Hox gene, demonstrating that the primary role of the Polycomb Group Complex is indeed Hox repression. This study advances our understanding of how neural stem cell programs operate at different axial levels of the central nervous system and may have implications also for stem cell and organoid biology.
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Affiliation(s)
- Shahrzad Bahrampour
- Department of Clinical and Experimental Medicine, Linkoping University, Linkoping, Sweden
| | - Carolin Jonsson
- Department of Clinical and Experimental Medicine, Linkoping University, Linkoping, Sweden
| | - Stefan Thor
- Department of Clinical and Experimental Medicine, Linkoping University, Linkoping, Sweden
- School of Biomedical Sciences, University of Queensland, St. Lucia, Queensland, Australia
- * E-mail:
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Abstract
SOX transcription factors participate in the specification, differentiation and activities of many cell types in development and beyond. The 20 mammalian family members are distributed into eight groups based on sequence identity, and while co-expressed same-group proteins often have redundant functions, different-group proteins typically have distinct functions. More than a handful of SOX proteins have pivotal roles in skeletogenesis. Heterozygous mutations in their genes cause human diseases, in which skeletal dysmorphism is a major feature, such as campomelic dysplasia (SOX9), or a minor feature, such as LAMSHF syndrome (SOX5) and Coffin-Siris-like syndromes (SOX4 and SOX11). Loss- and gain-of-function experiments in animal models have revealed that SOX4 and SOX11 (SOXC group) promote skeletal progenitor survival and control skeleton patterning and growth; SOX8 (SOXE group) delays the differentiation of osteoblast progenitors; SOX9 (SOXE group) is essential for chondrocyte fate maintenance and differentiation, and works in cooperation with SOX5 and SOX6 (SOXD group) and other types of transcription factors. These and other SOX proteins have also been proposed, mainly through in vitro experiments, to have key roles in other aspects of skeletogenesis, such as SOX2 in osteoblast stem cell self-renewal. We here review current knowledge of well-established and proposed skeletogenic roles of SOX proteins, their transcriptional and non-transcriptional actions, and their modes of regulation at the gene, RNA and protein levels. We also discuss gaps in knowledge and directions for future research to further decipher mechanisms underlying skeletogenesis in health and diseases and identify treatment options for skeletal malformation and degeneration diseases.
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Affiliation(s)
- Véronique Lefebvre
- The Children's Hospital of Philadelphia, Philadelphia, PA, United States.
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38
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Sox10 Regulates Plasticity of Epithelial Progenitors toward Secretory Units of Exocrine Glands. Stem Cell Reports 2019; 12:366-380. [PMID: 30713042 PMCID: PMC6373627 DOI: 10.1016/j.stemcr.2019.01.002] [Citation(s) in RCA: 43] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2018] [Revised: 12/31/2018] [Accepted: 01/02/2019] [Indexed: 12/16/2022] Open
Abstract
Understanding how epithelial progenitors within exocrine glands establish specific cell lineages and form complex functional secretory units is vital for organ regeneration. Here we identify the transcription factor Sox10 as essential for both the maintenance and differentiation of epithelial KIT+FGFR2b+ progenitors into secretory units, containing acinar, myoepithelial, and intercalated duct cells. The KIT/FGFR2b-Sox10 axis marks the earliest multi-potent and tissue-specific progenitors of exocrine glands. Genetic deletion of epithelial Sox10 leads to loss of secretory units, which reduces organ size and function, but the ductal tree is retained. Intriguingly, the remaining duct progenitors do not compensate for loss of Sox10 and lack plasticity to properly form secretory units. However, overexpression of Sox10 in these ductal progenitors enhances their plasticity toward KIT+ progenitors and induces differentiation into secretory units. Therefore, Sox10 controls plasticity and multi-potency of epithelial KIT+ cells in secretory organs, such as mammary, lacrimal, and salivary glands.
Sox10 marks the initial multi-potent KIT+ progenitors of exocrine glandular tissues KIT+ progenitors require Sox10 for their maintenance Sox10 is necessary for proper lineage development of secretory units Sox10 is sufficient to induce cell plasticity in non-KIT+ epithelial cells
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Bonatto Paese CL, Leite DJ, Schönauer A, McGregor AP, Russell S. Duplication and expression of Sox genes in spiders. BMC Evol Biol 2018; 18:205. [PMID: 30587109 PMCID: PMC6307133 DOI: 10.1186/s12862-018-1337-4] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2018] [Accepted: 12/17/2018] [Indexed: 02/02/2023] Open
Abstract
BACKGROUND The Sox family of transcription factors is an important part of the genetic 'toolbox' of all metazoans examined to date and is known to play important developmental roles in vertebrates and insects. However, outside the commonly studied Drosophila model little is known about the repertoire of Sox family transcription factors in other arthropod species. Here we characterise the Sox family in two chelicerate species, the spiders Parasteatoda tepidariorum and Stegodyphus mimosarum, which have experienced a whole genome duplication (WGD) in their evolutionary history. RESULTS We find that virtually all of the duplicate Sox genes have been retained in these spiders after the WGD. Analysis of the expression of Sox genes in P. tepidariorum embryos suggests that it is likely that some of these genes have neofunctionalised after duplication. Our expression analysis also strengthens the view that an orthologue of vertebrate Group B1 genes, SoxNeuro, is implicated in the earliest events of CNS specification in both vertebrates and invertebrates. In addition, a gene in the Dichaete/Sox21b class is dynamically expressed in the spider segment addition zone, suggestive of an ancient regulatory mechanism controlling arthropod segmentation as recently suggested for flies and beetles. Together with the recent analysis of Sox gene expression in the embryos of other arthropods, our findings support the idea of conserved functions for some of these genes, including a potential role for SoxC and SoxD genes in CNS development and SoxF in limb development. CONCLUSIONS Our study provides a new chelicerate perspective to understanding the evolution and function of Sox genes and how the retention of duplicates of such important tool-box genes after WGD has contributed to different aspects of spider embryogenesis. Future characterisation of the function of these genes in spiders will help us to better understand the evolution of the regulation of important developmental processes in arthropods and other metazoans including neurogenesis and segmentation.
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Affiliation(s)
- Christian L Bonatto Paese
- Department of Biological and Medical Sciences, Oxford Brookes University, Gipsy Lane, Oxford, OX3 0BP, UK
| | - Daniel J Leite
- Department of Biological and Medical Sciences, Oxford Brookes University, Gipsy Lane, Oxford, OX3 0BP, UK
| | - Anna Schönauer
- Department of Biological and Medical Sciences, Oxford Brookes University, Gipsy Lane, Oxford, OX3 0BP, UK
| | - Alistair P McGregor
- Department of Biological and Medical Sciences, Oxford Brookes University, Gipsy Lane, Oxford, OX3 0BP, UK.
| | - Steven Russell
- Department of Genetics, University of Cambridge, Downing Street, Cambridge, CB2 3EH, UK.
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40
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Zaletel I, Schwirtlich M, Perović M, Jovanović M, Stevanović M, Kanazir S, Puškaš N. Early Impairments of Hippocampal Neurogenesis in 5xFAD Mouse Model of Alzheimer’s Disease Are Associated with Altered Expression of SOXB Transcription Factors. J Alzheimers Dis 2018; 65:963-976. [DOI: 10.3233/jad-180277] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Affiliation(s)
- Ivan Zaletel
- Institute of Histology and Embryology “Aleksandar Đ Kostić”, School of Medicine, University of Belgrade, Belgrade, Serbia
| | - Marija Schwirtlich
- Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Belgrade, Serbia
| | - Milka Perović
- Institute for Biological Research “Siniša Stanković”, University of Belgrade, Belgrade, Serbia
| | - Mirna Jovanović
- Institute for Biological Research “Siniša Stanković”, University of Belgrade, Belgrade, Serbia
| | - Milena Stevanović
- Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Belgrade, Serbia
- University of Belgrade, Faculty of Biology, Belgrade, Serbia
- Serbian Academy of Sciences and Arts, Belgrade, Serbia
| | - Selma Kanazir
- Institute for Biological Research “Siniša Stanković”, University of Belgrade, Belgrade, Serbia
| | - Nela Puškaš
- Institute of Histology and Embryology “Aleksandar Đ Kostić”, School of Medicine, University of Belgrade, Belgrade, Serbia
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Liu CF, Angelozzi M, Haseeb A, Lefebvre V. SOX9 is dispensable for the initiation of epigenetic remodeling and the activation of marker genes at the onset of chondrogenesis. Development 2018; 145:dev164459. [PMID: 30021842 PMCID: PMC6078338 DOI: 10.1242/dev.164459] [Citation(s) in RCA: 52] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2018] [Accepted: 06/04/2018] [Indexed: 12/16/2022]
Abstract
SOX9 controls cell lineage fate and differentiation in major biological processes. It is known as a potent transcriptional activator of differentiation-specific genes, but its earliest targets and its contribution to priming chromatin for gene activation remain unknown. Here, we address this knowledge gap using chondrogenesis as a model system. By profiling the whole transcriptome and the whole epigenome of wild-type and Sox9-deficient mouse embryo limb buds, we uncover multiple structural and regulatory genes, including Fam101a, Myh14, Sema3c and Sema3d, as specific markers of precartilaginous condensation, and we provide evidence of their direct transactivation by SOX9. Intriguingly, we find that SOX9 helps remove epigenetic signatures of transcriptional repression and establish active-promoter and active-enhancer marks at precartilage- and cartilage-specific loci, but is not absolutely required to initiate these changes and activate transcription. Altogether, these findings widen our current knowledge of SOX9 targets in early chondrogenesis and call for new studies to identify the pioneer and transactivating factors that act upstream of or along with SOX9 to prompt chromatin remodeling and specific gene activation at the onset of chondrogenesis and other processes.
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Affiliation(s)
- Chia-Feng Liu
- Department of Cellular and Molecular Medicine, Cleveland Clinic Lerner Research Institute, Cleveland, OH 44195, USA
| | - Marco Angelozzi
- Department of Cellular and Molecular Medicine, Cleveland Clinic Lerner Research Institute, Cleveland, OH 44195, USA
| | - Abdul Haseeb
- Department of Cellular and Molecular Medicine, Cleveland Clinic Lerner Research Institute, Cleveland, OH 44195, USA
| | - Véronique Lefebvre
- Department of Cellular and Molecular Medicine, Cleveland Clinic Lerner Research Institute, Cleveland, OH 44195, USA
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42
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Navarro Quiroz E, Navarro Quiroz R, Ahmad M, Gomez Escorcia L, Villarreal JL, Fernandez Ponce C, Aroca Martinez G. Cell Signaling in Neuronal Stem Cells. Cells 2018; 7:E75. [PMID: 30011912 PMCID: PMC6070865 DOI: 10.3390/cells7070075] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2018] [Revised: 06/30/2018] [Accepted: 07/12/2018] [Indexed: 02/07/2023] Open
Abstract
The defining characteristic of neural stem cells (NSCs) is their ability to multiply through symmetric divisions and proliferation, and differentiation by asymmetric divisions, thus giving rise to different types of cells of the central nervous system (CNS). A strict temporal space control of the NSC differentiation is necessary, because its alterations are associated with neurological dysfunctions and, in some cases, death. This work reviews the current state of the molecular mechanisms that regulate the transcription in NSCs, organized according to whether the origin of the stimulus that triggers the molecular cascade in the CNS is internal (intrinsic factors) or whether it is the result of the microenvironment that surrounds the CNS (extrinsic factors).
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Affiliation(s)
- Elkin Navarro Quiroz
- Faculty of basic sciences and biomedical; Universidad Simón Bolívar, Barranquilla 080002, Colombia.
- School of Medicine, Universidad Rafael Nuñez, Cartagena 130001, Colombia.
| | - Roberto Navarro Quiroz
- Centro de Investigación en Salud para el Trópico, Universidad Cooperativa de Colombia, Santa Marta 470002, Colombia.
| | - Mostapha Ahmad
- Faculty of basic sciences and biomedical; Universidad Simón Bolívar, Barranquilla 080002, Colombia.
| | - Lorena Gomez Escorcia
- Faculty of basic sciences and biomedical; Universidad Simón Bolívar, Barranquilla 080002, Colombia.
| | | | | | - Gustavo Aroca Martinez
- Faculty of basic sciences and biomedical; Universidad Simón Bolívar, Barranquilla 080002, Colombia.
- Clinica de la Costa, Barranquilla 080002, Colombia.
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43
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Janssen R, Andersson E, Betnér E, Bijl S, Fowler W, Höök L, Leyhr J, Mannelqvist A, Panara V, Smith K, Tiemann S. Embryonic expression patterns and phylogenetic analysis of panarthropod sox genes: insight into nervous system development, segmentation and gonadogenesis. BMC Evol Biol 2018; 18:88. [PMID: 29884143 PMCID: PMC5994082 DOI: 10.1186/s12862-018-1196-z] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2017] [Accepted: 05/18/2018] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Sox (Sry-related high-mobility-group box) genes represent important factors in animal development. Relatively little, however, is known about the embryonic expression patterns and thus possible function(s) of Sox genes during ontogenesis in panarthropods (Arthropoda+Tardigrada+Onychophora). To date, studies have been restricted exclusively to higher insects, including the model system Drosophila melanogaster, with no comprehensive data available for any other arthropod group, or any tardigrade or onychophoran. RESULTS This study provides a phylogenetic analysis of panarthropod Sox genes and presents the first comprehensive analysis of embryonic expression patterns in the flour beetle Tribolium castaneum (Hexapoda), the pill millipede Glomeris marginata (Myriapoda), and the velvet worm, Euperipatoides kanangrensis (Onychophora). 24 Sox genes were identified and investigated: 7 in Euperipatoides, 8 in Glomeris, and 9 in Tribolium. Each species possesses at least one ortholog of each of the five expected Sox gene families, B, C, D, E, and F, many of which are differentially expressed during ontogenesis. CONCLUSION Sox gene expression (and potentially function) is highly conserved in arthropods and their closest relatives, the onychophorans. Sox B, C and D class genes appear to be crucial for nervous system development, while the Sox B genes Dichaete (D) and Sox21b likely play an additional conserved role in panarthropod segmentation. The Sox B gene Sox21a likely has a conserved function in foregut and Malpighian tubule development, at least in Hexapoda. The data further suggest that Sox D and E genes are involved in mesoderm differentiation, and that Sox E genes are involved in gonadal development. The new data expand our knowledge about the expression and implied function of Sox genes to Mandibulata (Myriapoda+Pancrustacea) and Panarthropoda (Arthropoda+Onychophora).
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Affiliation(s)
- Ralf Janssen
- Uppsala University, Department of Earth Sciences, Palaeobiology, Villavägen 16, 75236 Uppsala, Sweden
| | - Emil Andersson
- Uppsala University, Department of Earth Sciences, Palaeobiology, Villavägen 16, 75236 Uppsala, Sweden
| | - Ellinor Betnér
- Uppsala University, Department of Earth Sciences, Palaeobiology, Villavägen 16, 75236 Uppsala, Sweden
| | - Sifra Bijl
- Uppsala University, Department of Earth Sciences, Palaeobiology, Villavägen 16, 75236 Uppsala, Sweden
| | - Will Fowler
- Uppsala University, Department of Earth Sciences, Palaeobiology, Villavägen 16, 75236 Uppsala, Sweden
| | - Lars Höök
- Uppsala University, Department of Earth Sciences, Palaeobiology, Villavägen 16, 75236 Uppsala, Sweden
| | - Jake Leyhr
- Uppsala University, Department of Earth Sciences, Palaeobiology, Villavägen 16, 75236 Uppsala, Sweden
| | - Alexander Mannelqvist
- Uppsala University, Department of Earth Sciences, Palaeobiology, Villavägen 16, 75236 Uppsala, Sweden
| | - Virginia Panara
- Uppsala University, Department of Earth Sciences, Palaeobiology, Villavägen 16, 75236 Uppsala, Sweden
| | - Kate Smith
- Uppsala University, Department of Earth Sciences, Palaeobiology, Villavägen 16, 75236 Uppsala, Sweden
| | - Sydney Tiemann
- Uppsala University, Department of Earth Sciences, Palaeobiology, Villavägen 16, 75236 Uppsala, Sweden
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Unconventional function of an Achaete-Scute homolog as a terminal selector of nociceptive neuron identity. PLoS Biol 2018; 16:e2004979. [PMID: 29672507 PMCID: PMC5908064 DOI: 10.1371/journal.pbio.2004979] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2017] [Accepted: 03/12/2018] [Indexed: 11/19/2022] Open
Abstract
Proneural genes are among the most early-acting genes in nervous system development, instructing blast cells to commit to a neuronal fate. Drosophila Atonal and Achaete-Scute complex (AS-C) genes, as well as their vertebrate orthologs, are basic helix-loop-helix (bHLH) transcription factors with such proneural activity. We show here that a C. elegans AS-C homolog, hlh-4, functions in a fundamentally different manner. In the embryonic, larval, and adult nervous systems, hlh-4 is expressed exclusively in a single nociceptive neuron class, ADL, and its expression in ADL is maintained via transcriptional autoregulation throughout the life of the animal. However, in hlh-4 null mutants, the ADL neuron is generated and still appears neuronal in overall morphology and expression of panneuronal and pansensory features. Rather than acting as a proneural gene, we find that hlh-4 is required for the ADL neuron to function properly, to adopt its correct morphology, to express its unusually large repertoire of olfactory receptor-encoding genes, and to express other known features of terminal ADL identity, including neurotransmitter phenotype, neuropeptides, ion channels, and electrical synapse proteins. hlh-4 is sufficient to induce ADL identity features upon ectopic expression in other neuron types. The expression of ADL terminal identity features is directly controlled by HLH-4 via a phylogenetically conserved E-box motif, which, through bioinformatic analysis, we find to constitute a predictive feature of ADL-expressed terminal identity markers. The lineage that produces the ADL neuron was previously shown to require the conventional, transient proneural activity of another AS-C homolog, hlh-14, demonstrating sequential activities of distinct AS-C-type bHLH genes in neuronal specification. Taken together, we have defined here an unconventional function of an AS-C-type bHLH gene as a terminal selector of neuronal identity and we speculate that such function could be reflective of an ancestral function of an "ur-" bHLH gene.
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45
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Zhang S, Rasai A, Wang Y, Xu J, Bannerman P, Erol D, Tsegaye D, Wang A, Soulika A, Zhan X, Guo F. The Stem Cell Factor Sox2 Is a Positive Timer of Oligodendrocyte Development in the Postnatal Murine Spinal Cord. Mol Neurobiol 2018; 55:9001-9015. [PMID: 29623612 DOI: 10.1007/s12035-018-1035-7] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2017] [Accepted: 03/23/2018] [Indexed: 12/25/2022]
Abstract
Myelination in the central nervous system takes place predominantly during the postnatal development of humans and rodents by myelinating oligodendrocytes (OLs), which are differentiated from oligodendrocyte progenitor cells (OPCs). We recently reported that Sox2 is essential for developmental myelination in the murine brain and spinal cord. It is still controversial regarding the role of Sox2 in oligodendroglial lineage progression in the postnatal murine spinal cord. Analyses of a series of cell- and stage-specific Sox2 mutants reveal that Sox2 plays a biphasic role in regulating oligodendroglial lineage progression in the postnatal murine spinal cord. Sox2 controls the number of OPCs for subsequent differentiation through regulating their proliferation. In addition, Sox2 regulates the timing of OL differentiation and modulates the rate of oligodendrogenesis. Our experimental data prove that Sox2 is an intrinsic positive timer of oligodendroglial lineage progression and suggest that interventions affecting oligodendroglial Sox2 expression may be therapeutic for overcoming OPC differentiation arrest in dysmyelinating and demyelinating disorders.
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Affiliation(s)
- Sheng Zhang
- Institute for Pediatric Regenerative Medicine, Shriners Hospitals for Children/UC Davis School of Medicine, Sacramento, CA, 95817, USA.,Department of Neurology, School of Medicine, UC Davis, Davis, CA, 95817, USA
| | - Abeer Rasai
- Institute for Pediatric Regenerative Medicine, Shriners Hospitals for Children/UC Davis School of Medicine, Sacramento, CA, 95817, USA
| | - Yan Wang
- Institute for Pediatric Regenerative Medicine, Shriners Hospitals for Children/UC Davis School of Medicine, Sacramento, CA, 95817, USA.,Department of Neurology, School of Medicine, UC Davis, Davis, CA, 95817, USA
| | - Jie Xu
- Institute for Pediatric Regenerative Medicine, Shriners Hospitals for Children/UC Davis School of Medicine, Sacramento, CA, 95817, USA
| | - Peter Bannerman
- Institute for Pediatric Regenerative Medicine, Shriners Hospitals for Children/UC Davis School of Medicine, Sacramento, CA, 95817, USA.,Department of Cell Biology and Human Anatomy, School of Medicine, UC Davis, Davis, CA, 95817, USA
| | - Daffcar Erol
- Institute for Pediatric Regenerative Medicine, Shriners Hospitals for Children/UC Davis School of Medicine, Sacramento, CA, 95817, USA
| | - Danayit Tsegaye
- Institute for Pediatric Regenerative Medicine, Shriners Hospitals for Children/UC Davis School of Medicine, Sacramento, CA, 95817, USA
| | - Aijun Wang
- Institute for Pediatric Regenerative Medicine, Shriners Hospitals for Children/UC Davis School of Medicine, Sacramento, CA, 95817, USA.,Department of Surgery, School of Medicine, UC Davis, Davis, CA, 95817, USA
| | - Athena Soulika
- Institute for Pediatric Regenerative Medicine, Shriners Hospitals for Children/UC Davis School of Medicine, Sacramento, CA, 95817, USA.,Department of Dermatology, School of Medicine, UC Davis, Davis, CA, 95817, USA
| | - Xiangjiang Zhan
- Key Laboratory of Animal Ecology and Conservation Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China
| | - Fuzheng Guo
- Institute for Pediatric Regenerative Medicine, Shriners Hospitals for Children/UC Davis School of Medicine, Sacramento, CA, 95817, USA. .,Department of Neurology, School of Medicine, UC Davis, Davis, CA, 95817, USA. .,Department of Neurology, UC Davis School of Medicine, c/o Shriners Hospitals for Children, Room 601A, 2425 Stockton Blvd, Sacramento, CA, 95817, USA.
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46
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Fullard JF, Giambartolomei C, Hauberg ME, Xu K, Voloudakis G, Shao Z, Bare C, Dudley JT, Mattheisen M, Robakis NK, Haroutunian V, Roussos P. Open chromatin profiling of human postmortem brain infers functional roles for non-coding schizophrenia loci. Hum Mol Genet 2017; 26:1942-1951. [PMID: 28335009 DOI: 10.1093/hmg/ddx103] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2017] [Accepted: 03/10/2017] [Indexed: 01/03/2023] Open
Abstract
Open chromatin provides access to DNA-binding proteins for the correct spatiotemporal regulation of gene expression. Mapping chromatin accessibility has been widely used to identify the location of cis regulatory elements (CREs) including promoters and enhancers. CREs show tissue- and cell-type specificity and disease-associated variants are often enriched for CREs in the tissues and cells that pertain to a given disease. To better understand the role of CREs in neuropsychiatric disorders we applied the Assay for Transposase Accessible Chromatin followed by sequencing (ATAC-seq) to neuronal and non-neuronal nuclei isolated from frozen postmortem human brain by fluorescence-activated nuclear sorting (FANS). Most of the identified open chromatin regions (OCRs) are differentially accessible between neurons and non-neurons, and show enrichment with known cell type markers, promoters and enhancers. Relative to those of non-neurons, neuronal OCRs are more evolutionarily conserved and are enriched in distal regulatory elements. Transcription factor (TF) footprinting analysis identifies differences in the regulome between neuronal and non-neuronal cells and ascribes putative functional roles to a number of non-coding schizophrenia (SCZ) risk variants. Among the identified variants is a Single Nucleotide Polymorphism (SNP) proximal to the gene encoding SNX19. In vitro experiments reveal that this SNP leads to an increase in transcriptional activity. As elevated expression of SNX19 has been associated with SCZ, our data provide evidence that the identified SNP contributes to disease. These results represent the first analysis of OCRs and TF-binding sites in distinct populations of postmortem human brain cells and further our understanding of the regulome and the impact of neuropsychiatric disease-associated genetic risk variants.
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Affiliation(s)
- John F Fullard
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Claudia Giambartolomei
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Mads E Hauberg
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.,Department of Biomedicine.,Centre for Integrative Sequencing (iSEQ), Aarhus University, Aarhus, Denmark.,The Lundbeck Foundation Initiative of Integrative Psychiatric Research (iPSYCH), Denmark
| | - Ke Xu
- Department of Genetics and Genomic Science and Institute for Multiscale Biology
| | - Georgios Voloudakis
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Zhiping Shao
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.,Department of Neuroscience.,Center for Molecular Biology and Genetics of Neurodegeneration
| | - Christopher Bare
- Flow Cytometry Center of Research Excellence, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Joel T Dudley
- Department of Genetics and Genomic Science and Institute for Multiscale Biology
| | - Manuel Mattheisen
- Department of Biomedicine.,Centre for Integrative Sequencing (iSEQ), Aarhus University, Aarhus, Denmark.,The Lundbeck Foundation Initiative of Integrative Psychiatric Research (iPSYCH), Denmark
| | - Nikolaos K Robakis
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.,Department of Neuroscience.,Center for Molecular Biology and Genetics of Neurodegeneration
| | - Vahram Haroutunian
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.,Department of Neuroscience.,Mental Illness Research, Education, and Clinical Center (VISN 2 South), James J. Peters VA Medical Center, Bronx, NY, USA
| | - Panos Roussos
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.,Department of Genetics and Genomic Science and Institute for Multiscale Biology.,Mental Illness Research, Education, and Clinical Center (VISN 2 South), James J. Peters VA Medical Center, Bronx, NY, USA
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47
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Chd7 Collaborates with Sox2 to Regulate Activation of Oligodendrocyte Precursor Cells after Spinal Cord Injury. J Neurosci 2017; 37:10290-10309. [PMID: 28931573 DOI: 10.1523/jneurosci.1109-17.2017] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2017] [Revised: 08/09/2017] [Accepted: 09/12/2017] [Indexed: 12/13/2022] Open
Abstract
Oligodendrocyte precursor cells (OPCs) act as a reservoir of new oligodendrocytes (OLs) in homeostatic and pathological conditions. OPCs are activated in response to injury to generate myelinating OLs, but the underlying mechanisms remain poorly understood. Here, we show that chromodomain helicase DNA binding protein 7 (Chd7) regulates OPC activation after spinal cord injury (SCI). Chd7 is expressed in OPCs in the adult spinal cord and its expression is upregulated with a concomitant increase in Sox2 expression after SCI. OPC-specific ablation of Chd7 in injured mice leads to reduced OPC proliferation, the loss of OPC identity, and impaired OPC differentiation. Ablation of Chd7 or Sox2 in cultured OPCs shows similar phenotypes to those observed in Chd7 knock-out mice. Chd7 and Sox2 form a complex in OPCs and bind to the promoters or enhancers of the regulator of cell cycle (Rgcc) and protein kinase Cθ (PKCθ) genes, thereby inducing their expression. The expression of Rgcc and PKCθ is reduced in the OPCs of the injured Chd7 knock-out mice. In cultured OPCs, overexpression and knock-down of Rgcc or PKCθ promote and suppress OPC proliferation, respectively. Furthermore, overexpression of both Rgcc and PKCθ rescues the Chd7 deletion phenotypes. Chd7 is thus a key regulator of OPC activation, in which it cooperates with Sox2 and acts via direct induction of Rgcc and PKCθ expression.SIGNIFICANCE STATEMENT Spinal cord injury (SCI) leads to oligodendrocyte (OL) loss and demyelination, along with neuronal death, resulting in impairment of motor or sensory functions. Oligodendrocyte precursor cells (OPCs) activated in response to injury are potential sources of OL replacement and are thought to contribute to remyelination and functional recovery after SCI. However, the molecular mechanisms underlying OPC activation, especially its epigenetic regulation, remain largely unclear. We demonstrate here that the chromatin remodeler chromodomain helicase DNA binding protein 7 (Chd7) regulates the proliferation and identity of OPCs after SCI. We have further identified regulator of cell cycle (Rgcc) and protein kinase Cθ (PKCθ) as novel targets of Chd7 for OPC activation.
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Dvorakova M, Jahan I, Macova I, Chumak T, Bohuslavova R, Syka J, Fritzsch B, Pavlinkova G. Incomplete and delayed Sox2 deletion defines residual ear neurosensory development and maintenance. Sci Rep 2016; 6:38253. [PMID: 27917898 PMCID: PMC5137136 DOI: 10.1038/srep38253] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2016] [Accepted: 11/07/2016] [Indexed: 11/09/2022] Open
Abstract
The role of Sox2 in neurosensory development is not yet fully understood. Using mice with conditional Islet1-cre mediated deletion of Sox2, we explored the function of Sox2 in neurosensory development in a model with limited cell type diversification, the inner ear. In Sox2 conditional mutants, neurons initially appear to form normally, whereas late- differentiating neurons of the cochlear apex never form. Variable numbers of hair cells differentiate in the utricle, saccule, and cochlear base but sensory epithelium formation is completely absent in the apex and all three cristae of the semicircular canal ampullae. Hair cells differentiate only in sensory epithelia known or proposed to have a lineage relationship of neurons and hair cells. All initially formed neurons lacking hair cell targets die by apoptosis days after they project toward non-existing epithelia. Therefore, late neuronal development depends directly on Sox2 for differentiation and on the survival of hair cells, possibly derived from common neurosensory precursors.
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Affiliation(s)
- Martina Dvorakova
- Institute of Biotechnology CAS, Prague, Czechia
- Faculty of Science, Charles University, Prague, Czechia
| | - Israt Jahan
- Department of Biology, University of Iowa, Iowa City, IA, USA
| | - Iva Macova
- Institute of Biotechnology CAS, Prague, Czechia
- Faculty of Science, Charles University, Prague, Czechia
| | | | | | - Josef Syka
- Institute of Experimental Medicine CAS, Prague, Czechia
| | - Bernd Fritzsch
- Department of Biology, University of Iowa, Iowa City, IA, USA
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49
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Hobert O. A map of terminal regulators of neuronal identity in Caenorhabditis elegans. WILEY INTERDISCIPLINARY REVIEWS-DEVELOPMENTAL BIOLOGY 2016; 5:474-98. [PMID: 27136279 PMCID: PMC4911249 DOI: 10.1002/wdev.233] [Citation(s) in RCA: 69] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/02/2016] [Revised: 02/07/2016] [Accepted: 02/21/2016] [Indexed: 12/31/2022]
Abstract
Our present day understanding of nervous system development is an amalgam of insights gained from studying different aspects and stages of nervous system development in a variety of invertebrate and vertebrate model systems, with each model system making its own distinctive set of contributions. One aspect of nervous system development that has been among the most extensively studied in the nematode Caenorhabditis elegans is the nature of the gene regulatory programs that specify hardwired, terminal cellular identities. I first summarize a number of maps (anatomical, functional, and molecular) that describe the terminal identity of individual neurons in the C. elegans nervous system. I then provide a comprehensive summary of regulatory factors that specify terminal identities in the nervous system, synthesizing these past studies into a regulatory map of cellular identities in the C. elegans nervous system. This map shows that for three quarters of all neurons in the C. elegans nervous system, regulatory factors that control terminal identity features are known. In-depth studies of specific neuron types have revealed that regulatory factors rarely act alone, but rather act cooperatively in neuron-type specific combinations. In most cases examined so far, distinct, biochemically unlinked terminal identity features are coregulated via cooperatively acting transcription factors, termed terminal selectors, but there are also cases in which distinct identity features are controlled in a piecemeal fashion by independent regulatory inputs. The regulatory map also illustrates that identity-defining transcription factors are reemployed in distinct combinations in different neuron types. However, the same transcription factor can drive terminal differentiation in neurons that are unrelated by lineage, unrelated by function, connectivity and neurotransmitter deployment. Lastly, the regulatory map illustrates the preponderance of homeodomain transcription factors in the control of terminal identities, suggesting that these factors have ancient, phylogenetically conserved roles in controlling terminal neuronal differentiation in the nervous system. WIREs Dev Biol 2016, 5:474-498. doi: 10.1002/wdev.233 For further resources related to this article, please visit the WIREs website.
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Affiliation(s)
- Oliver Hobert
- Department of Biological Sciences, Howard Hughes Medical Institute, Columbia University, New York, NY, USA
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50
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Richards GS, Rentzsch F. Regulation of Nematostella neural progenitors by SoxB, Notch and bHLH genes. Development 2016; 142:3332-42. [PMID: 26443634 PMCID: PMC4631755 DOI: 10.1242/dev.123745] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Notch signalling, SoxB and Group A bHLH 'proneural' genes are conserved regulators of the neurogenic program in many bilaterians. However, the ancestry of their functions and interactions is not well understood. We address this question in the sea anemone Nematostella vectensis, a representative of the Cnidaria, the sister clade to the Bilateria. It has previously been found that the SoxB orthologue NvSoxB(2) is expressed in neural progenitor cells (NPCs) in Nematostella and promotes the development of both neurons and nematocytes, whereas Notch signalling has been implicated in the negative regulation of neurons and the positive regulation of nematocytes. Here, we clarify the role of Notch by reporting that inhibition of Notch signalling increases the numbers of both neurons and nematocytes, as well as increasing the number of NvSoxB(2)-expressing cells. This suggests that Notch restricts neurogenesis by limiting the generation of NPCs. We then characterise NvAth-like (Atonal/Neurogenin family) as a positive regulator of neurogenesis that is co-expressed with NvSoxB(2) in a subset of dividing NPCs, while we find that NvAshA (Achaete-scute family) and NvSoxB(2) are co-expressed in non-dividing cells only. Reciprocal knockdown experiments reveal a mutual requirement for NvSoxB(2) and NvAth-like in neural differentiation; however, the primary expression of each gene is independent of the other. Together, these data demonstrate that Notch signalling and NvSoxB(2) regulate Nematostella neural progenitors via parallel yet interacting mechanisms; with different aspects of these interactions being shared with Drosophila and/or vertebrate neurogenesis.
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Affiliation(s)
- Gemma Sian Richards
- Sars Centre for Marine Molecular Biology, University of Bergen, Thormøhlensgate 55, Bergen N-5008, Norway
| | - Fabian Rentzsch
- Sars Centre for Marine Molecular Biology, University of Bergen, Thormøhlensgate 55, Bergen N-5008, Norway
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