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1
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Han F, Zhou X, Liu L, Yang B, Liu P, Xu E, Tang Z, Zhang H. GLTSCR1 deficiency promotes colorectal cancer development through regulating non-homologous end joining. Oncogene 2024; 43:3517-3531. [PMID: 39394449 DOI: 10.1038/s41388-024-03179-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2024] [Revised: 09/18/2024] [Accepted: 09/23/2024] [Indexed: 10/13/2024]
Abstract
Non-homologous end joining (NHEJ), as one major pathway of DNA double-strand break (DSB) repair, could cause genomic instability, which plays pivotal roles in cancer development. While, chromatin remodeling complexes dictate the selection and orchestration of DSB repair pathways by regulating chromatin dynamics. However, the crosstalk between NHEJ and chromatin remodeling in cancer progress remains unclear. In this study, deficiency of GLTSCR1 causes resistance to DNA damage in colorectal cancer (CRC) cells by promoting NHEJ repair efficiency. Mechanistically, GLTSCR1 interacts with BRD9 to engage in the assembly of the non-canonical BAF complex (GBAF). However, GLTSCR1 deficiency disrupts GBAF and triggers the ubiquitination degradation of BRD9. Furthermore, GLTSCR1 deficiency causes aberrant opening in the promoter region of NHEJ repair-associated genes, which promotes CRC development. While, GLTSCR1 and its binding partner BRD9 are not directly involved in assembling NHEJ repair machinery; instead, they regulate the DNA accessibility of NHEJ repair-associated genes. Collectively, our findings confirm GLTSCR1 deficiency as a critical regulatory event of the NHEJ pathway in CRC development, which might require different therapeutic strategy for GLTSCR1 wild-type and mutant CRC.
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Affiliation(s)
- Fengyan Han
- Department of Pathology and International Institutes of Medicine, The Fourth Affiliated Hospital (Yiwu), Zhejiang University School of Medicine, Hangzhou, 310058, China.
- School of Basic Medical Science, The Fourth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, China.
| | - Xiaoxu Zhou
- Women's Reproductive Health Key Laboratory of Zhejiang Province, Women's Hospital and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310006, China
| | - Lu Liu
- Department of Pathology and International Institutes of Medicine, The Fourth Affiliated Hospital (Yiwu), Zhejiang University School of Medicine, Hangzhou, 310058, China
| | - Beibei Yang
- Department of Pathology, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310006, China
| | - Pengyuan Liu
- Sir Run Run Shaw Hospital and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310016, China
| | - Enping Xu
- Department of Pathology and International Institutes of Medicine, The Fourth Affiliated Hospital (Yiwu), Zhejiang University School of Medicine, Hangzhou, 310058, China.
| | - Zhe Tang
- Department of Surgery, The Fourth Affiliated Hospital, International Institutes of Medicine, Zhejiang University School of Medicine, Yiwu, 322000, China.
- Department of Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, China.
| | - Honghe Zhang
- Department of Pathology and International Institutes of Medicine, The Fourth Affiliated Hospital (Yiwu), Zhejiang University School of Medicine, Hangzhou, 310058, China.
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2
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Chow CFW, Ghosh S, Hadarovich A, Toth-Petroczy A. SHARK enables sensitive detection of evolutionary homologs and functional analogs in unalignable and disordered sequences. Proc Natl Acad Sci U S A 2024; 121:e2401622121. [PMID: 39383002 PMCID: PMC11494347 DOI: 10.1073/pnas.2401622121] [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: 01/24/2024] [Accepted: 08/30/2024] [Indexed: 10/11/2024] Open
Abstract
Intrinsically disordered regions (IDRs) are structurally flexible protein segments with regulatory functions in multiple contexts, such as in the assembly of biomolecular condensates. Since IDRs undergo more rapid evolution than ordered regions, identifying homology of such poorly conserved regions remains challenging for state-of-the-art alignment-based methods that rely on position-specific conservation of residues. Thus, systematic functional annotation and evolutionary analysis of IDRs have been limited, despite them comprising ~21% of proteins. To accurately assess homology between unalignable sequences, we developed an alignment-free sequence comparison algorithm, SHARK (Similarity/Homology Assessment by Relating K-mers). We trained SHARK-dive, a machine learning homology classifier, which achieved superior performance to standard alignment-based approaches in assessing evolutionary homology in unalignable sequences. Furthermore, it correctly identified dissimilar but functionally analogous IDRs in IDR-replacement experiments reported in the literature, whereas alignment-based tools were incapable of detecting such functional relationships. SHARK-dive not only predicts functionally similar IDRs at a proteome-wide scale but also identifies cryptic sequence properties and motifs that drive remote homology and analogy, thereby providing interpretable and experimentally verifiable hypotheses of the sequence determinants that underlie such relationships. SHARK-dive acts as an alternative to alignment to facilitate systematic analysis and functional annotation of the unalignable protein universe.
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Affiliation(s)
- Chi Fung Willis Chow
- Max Planck Institute of Molecular Cell Biology and Genetics, Dresden01307, Germany
- Center for Systems Biology Dresden, Dresden01307, Germany
- Cluster of Excellence Physics of Life, Technische Universität Dresden, Dresden01062, Germany
| | - Soumyadeep Ghosh
- Max Planck Institute of Molecular Cell Biology and Genetics, Dresden01307, Germany
- Center for Systems Biology Dresden, Dresden01307, Germany
| | - Anna Hadarovich
- Max Planck Institute of Molecular Cell Biology and Genetics, Dresden01307, Germany
- Center for Systems Biology Dresden, Dresden01307, Germany
| | - Agnes Toth-Petroczy
- Max Planck Institute of Molecular Cell Biology and Genetics, Dresden01307, Germany
- Center for Systems Biology Dresden, Dresden01307, Germany
- Cluster of Excellence Physics of Life, Technische Universität Dresden, Dresden01062, Germany
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3
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Gourisankar S, Krokhotin A, Wenderski W, Crabtree GR. Context-specific functions of chromatin remodellers in development and disease. Nat Rev Genet 2024; 25:340-361. [PMID: 38001317 PMCID: PMC11867214 DOI: 10.1038/s41576-023-00666-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/27/2023] [Indexed: 11/26/2023]
Abstract
Chromatin remodellers were once thought to be highly redundant and nonspecific in their actions. However, recent human genetic studies demonstrate remarkable biological specificity and dosage sensitivity of the thirty-two adenosine triphosphate (ATP)-dependent chromatin remodellers encoded in the human genome. Mutations in remodellers produce many human developmental disorders and cancers, motivating efforts to investigate their distinct functions in biologically relevant settings. Exquisitely specific biological functions seem to be an emergent property in mammals, and in many cases are based on the combinatorial assembly of subunits and the generation of stable, composite surfaces. Critical interactions between remodelling complex subunits, the nucleosome and other transcriptional regulators are now being defined from structural and biochemical studies. In addition, in vivo analyses of remodellers at relevant genetic loci have provided minute-by-minute insights into their dynamics. These studies are proposing new models for the determinants of remodeller localization and function on chromatin.
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Affiliation(s)
- Sai Gourisankar
- Department of Pathology, Stanford University, Stanford, CA, USA
- Department of Chemical Engineering, Stanford University, Stanford, CA, USA
| | - Andrey Krokhotin
- Department of Pathology, Stanford University, Stanford, CA, USA
- Department of Developmental Biology, Stanford University, Stanford, CA, USA
| | - Wendy Wenderski
- Department of Pathology, Stanford University, Stanford, CA, USA
- Department of Developmental Biology, Stanford University, Stanford, CA, USA
| | - Gerald R Crabtree
- Department of Pathology, Stanford University, Stanford, CA, USA.
- Department of Developmental Biology, Stanford University, Stanford, CA, USA.
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4
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Hernández-Oliveras A, Zarain-Herzberg A. The role of Ca 2+-signaling in the regulation of epigenetic mechanisms. Cell Calcium 2024; 117:102836. [PMID: 37988873 DOI: 10.1016/j.ceca.2023.102836] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2023] [Revised: 11/10/2023] [Accepted: 11/16/2023] [Indexed: 11/23/2023]
Abstract
Epigenetic mechanisms regulate multiple cell functions like gene expression and chromatin conformation and stability, and its misregulation could lead to several diseases including cancer. Epigenetic drugs are currently under investigation in a broad range of diseases, but the cellular processes involved in regulating epigenetic mechanisms are not fully understood. Calcium (Ca2+) signaling regulates several cellular mechanisms such as proliferation, gene expression, and metabolism, among others. Moreover, Ca2+ signaling is also involved in diseases such as neurological disorders, cardiac, and cancer. Evidence indicates that Ca2+ signaling and epigenetics are involved in the same cellular functions, which suggests a possible interplay between both mechanisms. Ca2+-activated transcription factors regulate the recruitment of chromatin remodeling complexes into their target genes, and Ca2+-sensing proteins modulate their activity and intracellular localization. Thus, Ca2+ signaling is an important regulator of epigenetic mechanisms. Moreover, Ca2+ signaling activates epigenetic mechanisms that in turn regulate genes involved in Ca2+ signaling, suggesting possible feedback between both mechanisms. The understanding of how epigenetics are regulated could lead to developing better therapeutical approaches.
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Affiliation(s)
- Andrés Hernández-Oliveras
- Departamento de Bioquímica, Facultad de Medicina, Universidad Nacional Autónoma de México, 04510, Mexico City, Mexico
| | - Angel Zarain-Herzberg
- Departamento de Bioquímica, Facultad de Medicina, Universidad Nacional Autónoma de México, 04510, Mexico City, Mexico.
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5
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Gourisankar S, Wenderski W, Paulo JA, Kim SH, Roepke K, Ellis C, Gygi SP, Crabtree GR. Synaptic Activity Causes Minute-scale Changes in BAF Complex Composition and Function. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.10.13.562244. [PMID: 37873481 PMCID: PMC10592824 DOI: 10.1101/2023.10.13.562244] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/25/2023]
Abstract
Genes encoding subunits of the SWI/SNF or BAF ATP-dependent chromatin remodeling complex are among the most enriched for deleterious de novo mutations in intellectual disabilities and autism spectrum disorder, but the causative molecular pathways are not fully known 1,2 . Synaptic activity in neurons is critical for learning and memory and proper neural development 3 . Neural activity prompts calcium influx and transcription within minutes, facilitated in the nucleus by various transcription factors (TFs) and chromatin modifiers 4 . While BAF is required for activity-dependent developmental processes such as dendritic outgrowth 5-7 , the immediate molecular consequences of neural activity on BAF complexes and their functions are unknown. Here we mapped minute-scale biochemical consequences of neural activity, modeled by membrane depolarization of embryonic mouse primary cortical neurons, on BAF complexes. We used acute chemical perturbations of BAF ATPase activity and kinase signaling to define the activity-dependent effects on BAF complexes and activity-dependent BAF functions. Our studies found that BAF complexes change in subunit composition and are selectively phosphorylated within 10 minutes of depolarization. Increased levels of the core PBAF subunit Baf200/ Arid2 , uniquely containing an RFX-like DNA-binding domain, are concurrent with ATPase-dependent opening of chromatin at RFX/X-box motifs. Changes in BAF composition and phosphorylation lead to the regulation of chromatin accessibility for critical neurogenesis TFs. These biochemical effects are a convergent phenomenon downstream of multiple growth factor signaling pathways in mouse neurons and fibroblasts suggesting that BAF integrates signaling information from the membrane. In support of such a membrane-to-nucleus signaling cascade, we also identified a BAF-interacting kinase, Dclk2, whose inhibition attenuates BAF phosphorylation selectively. Our findings support a direct role of BAF complexes in responding to synaptic activity to regulate TF binding and transcription.
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6
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Enck JR, Olson EC. Calcium Signaling during Cortical Apical Dendrite Initiation: A Role for Cajal-Retzius Neurons. Int J Mol Sci 2023; 24:12965. [PMID: 37629145 PMCID: PMC10455361 DOI: 10.3390/ijms241612965] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2023] [Revised: 08/15/2023] [Accepted: 08/17/2023] [Indexed: 08/27/2023] Open
Abstract
The apical dendrite of a cortical projection neuron (CPN) is generated from the leading process of the migrating neuron as the neuron completes migration. This transformation occurs in the cortical marginal zone (MZ), a layer that contains the Cajal-Retzius neurons and their axonal projections. Cajal-Retzius neurons (CRNs) are well known for their critical role in secreting Reelin, a glycoprotein that controls dendritogenesis and cell positioning in many regions of the developing brain. In this study, we examine the possibility that CRNs in the MZ may provide additional signals to arriving CPNs, that may promote the maturation of CPNs and thus shape the development of the cortex. We use whole embryonic hemisphere explants and multiphoton microscopy to confirm that CRNs display intracellular calcium transients of <1-min duration and high amplitude during early corticogenesis. In contrast, developing CPNs do not show high-amplitude calcium transients, but instead show a steady increase in intracellular calcium that begins at the time of dendritic initiation, when the leading process of the migrating CPN is encountering the MZ. The possible existence of CRN to CPN communication was revealed by the application of veratridine, a sodium channel activator, which has been shown to preferentially stimulate more mature cells in the MZ at an early developmental time. Surprisingly, veratridine application also triggers large calcium transients in CPNs, which can be partially blocked by a cocktail of antagonists that block glutamate and glycine receptor activation. These findings outline a model in which CRN spontaneous activity triggers the release of glutamate and glycine, neurotransmitters that can trigger intracellular calcium elevations in CPNs. These elevations begin as CPNs initiate dendritogenesis and continue as waves in the post-migratory cells. Moreover, we show that the pharmacological blockade of glutamatergic signaling disrupts migration, while forced expression of a bacterial voltage-gated calcium channel (CavMr) in the migrating neurons promotes dendritic growth and migration arrest. The identification of CRN to CPN signaling during early development provides insight into the observation that many autism-linked genes encode synaptic proteins that, paradoxically, are expressed in the developing cortex well before the appearance of synapses and the establishment of functional circuits.
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Affiliation(s)
| | - Eric C. Olson
- Department of Neuroscience and Physiology, State University of New York Upstate Medical University, 505 Irving Ave., Syracuse, NY 13210, USA;
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7
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Kobiec T, Mardaraz C, Toro-Urrego N, Kölliker-Frers R, Capani F, Otero-Losada M. Neuroprotection in metabolic syndrome by environmental enrichment. A lifespan perspective. Front Neurosci 2023; 17:1214468. [PMID: 37638319 PMCID: PMC10447983 DOI: 10.3389/fnins.2023.1214468] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2023] [Accepted: 07/17/2023] [Indexed: 08/29/2023] Open
Abstract
Metabolic syndrome (MetS) is defined by the concurrence of different metabolic conditions: obesity, hypertension, dyslipidemia, and hyperglycemia. Its incidence has been increasingly rising over the past decades and has become a global health problem. MetS has deleterious consequences on the central nervous system (CNS) and neurological development. MetS can last several years or be lifelong, affecting the CNS in different ways and treatments can help manage condition, though there is no known cure. The early childhood years are extremely important in neurodevelopment, which extends beyond, encompassing a lifetime. Neuroplastic changes take place all life through - childhood, adolescence, adulthood, and old age - are highly sensitive to environmental input. Environmental factors have an important role in the etiopathogenesis and treatment of MetS, so environmental enrichment (EE) stands as a promising non-invasive therapeutic approach. While the EE paradigm has been designed for animal housing, its principles can be and actually are applied in cognitive, sensory, social, and physical stimulation programs for humans. Here, we briefly review the central milestones in neurodevelopment at each life stage, along with the research studies carried out on how MetS affects neurodevelopment at each life stage and the contributions that EE models can provide to improve health over the lifespan.
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Affiliation(s)
- Tamara Kobiec
- Facultad de Psicología, Centro de Investigaciones en Psicología y Psicopedagogía, Pontificia Universidad Católica Argentina, Buenos Aires, Argentina
- Centro de Altos Estudios en Ciencias Humanas y de la Salud, Universidad Abierta Interamericana, Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires, Argentina
| | - Claudia Mardaraz
- Centro de Altos Estudios en Ciencias Humanas y de la Salud, Universidad Abierta Interamericana, Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires, Argentina
| | - Nicolás Toro-Urrego
- Centro de Altos Estudios en Ciencias Humanas y de la Salud, Universidad Abierta Interamericana, Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires, Argentina
| | - Rodolfo Kölliker-Frers
- Centro de Altos Estudios en Ciencias Humanas y de la Salud, Universidad Abierta Interamericana, Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires, Argentina
| | - Francisco Capani
- Centro de Altos Estudios en Ciencias Humanas y de la Salud, Universidad Abierta Interamericana, Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires, Argentina
- Facultad de Ciencias de la Salud, Instituto de Ciencias Biomédicas, Universidad Autónoma de Chile, Santiago, Chile
| | - Matilde Otero-Losada
- Centro de Altos Estudios en Ciencias Humanas y de la Salud, Universidad Abierta Interamericana, Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires, Argentina
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8
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Otto JE, Ursu O, Wu AP, Winter EB, Cuoco MS, Ma S, Qian K, Michel BC, Buenrostro JD, Berger B, Regev A, Kadoch C. Structural and functional properties of mSWI/SNF chromatin remodeling complexes revealed through single-cell perturbation screens. Mol Cell 2023; 83:1350-1367.e7. [PMID: 37028419 DOI: 10.1016/j.molcel.2023.03.013] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2022] [Revised: 02/07/2023] [Accepted: 03/10/2023] [Indexed: 04/09/2023]
Abstract
The mammalian SWI/SNF (mSWI/SNF or BAF) family of chromatin remodeling complexes play critical roles in regulating DNA accessibility and gene expression. The three final-form subcomplexes-cBAF, PBAF, and ncBAF-are distinct in biochemical componentry, chromatin targeting, and roles in disease; however, the contributions of their constituent subunits to gene expression remain incompletely defined. Here, we performed Perturb-seq-based CRISPR-Cas9 knockout screens targeting mSWI/SNF subunits individually and in select combinations, followed by single-cell RNA-seq and SHARE-seq. We uncovered complex-, module-, and subunit-specific contributions to distinct regulatory networks and defined paralog subunit relationships and shifted subcomplex functions upon perturbations. Synergistic, intra-complex genetic interactions between subunits reveal functional redundancy and modularity. Importantly, single-cell subunit perturbation signatures mapped across bulk primary human tumor expression profiles both mirror and predict cBAF loss-of-function status in cancer. Our findings highlight the utility of Perturb-seq to dissect disease-relevant gene regulatory impacts of heterogeneous, multi-component master regulatory complexes.
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Affiliation(s)
- Jordan E Otto
- Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Chemical Biology Program, Harvard University, Cambridge, MA, USA
| | - Oana Ursu
- Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Alexander P Wu
- Broad Institute of MIT and Harvard, Cambridge, MA, USA; Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA, USA; Department of Mathematics, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Evan B Winter
- Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | | | - Sai Ma
- Broad Institute of MIT and Harvard, Cambridge, MA, USA; Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA
| | - Kristin Qian
- Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Biological and Biomedical Sciences Program, Harvard Medical School, Boston, MA, USA
| | - Brittany C Michel
- Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Biological and Biomedical Sciences Program, Harvard Medical School, Boston, MA, USA
| | - Jason D Buenrostro
- Broad Institute of MIT and Harvard, Cambridge, MA, USA; Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA
| | - Bonnie Berger
- Broad Institute of MIT and Harvard, Cambridge, MA, USA; Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA, USA; Department of Mathematics, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Aviv Regev
- Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA; Howard Hughes Medical Institute, Chevy Chase, MD, UA.
| | - Cigall Kadoch
- Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Chemical Biology Program, Harvard University, Cambridge, MA, USA; Howard Hughes Medical Institute, Chevy Chase, MD, UA.
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9
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Perdomo-Sabogal A, Trakooljul N, Hadlich F, Murani E, Wimmers K, Ponsuksili S. DNA methylation landscapes from pig's limbic structures underline regulatory mechanisms relevant for brain plasticity. Sci Rep 2022; 12:16293. [PMID: 36175587 PMCID: PMC9522933 DOI: 10.1038/s41598-022-20682-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Accepted: 09/16/2022] [Indexed: 11/09/2022] Open
Abstract
Epigenetic dynamics are essential for reconciling stress-induced responses in neuro-endocrine routes between the limbic brain and adrenal gland. CpG methylation associates with the initiation and end of regulatory mechanisms underlying responses critical for survival, and learning. Using Reduced Representation Bisulfite Sequencing, we identified methylation changes of functional relevance for mediating tissue-specific responses in the hippocampus, amygdala, hypothalamus, and adrenal gland in pigs. We identified 4186 differentially methylated CpGs across all tissues, remarkably, enriched for promoters of transcription factors (TFs) of the homeo domain and zinc finger classes. We also detected 5190 differentially methylated regions (DMRs, 748 Mb), with about half unique to a single pairwise. Two structures, the hypothalamus and the hippocampus, displayed 860 unique brain-DMRs, with many linked to regulation of chromatin, nervous development, neurogenesis, and cell-to-cell communication. TF binding motifs for TFAP2A and TFAP2C are enriched amount DMRs on promoters of other TFs, suggesting their role as master regulators, especially for pathways essential in long-term brain plasticity, memory, and stress responses. Our results reveal sets of TF that, together with CpG methylation, may serve as regulatory switches to modulate limbic brain plasticity and brain-specific molecular genetics in pigs.
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Affiliation(s)
- Alvaro Perdomo-Sabogal
- Research Institute for Farm Animal Biology (FBN), Institute for Genome Biology, Wilhelm-Stahl-Allee 2, 18196, Dummerstorf, Germany
| | - Nares Trakooljul
- Research Institute for Farm Animal Biology (FBN), Institute for Genome Biology, Wilhelm-Stahl-Allee 2, 18196, Dummerstorf, Germany
| | - Frieder Hadlich
- Research Institute for Farm Animal Biology (FBN), Institute for Genome Biology, Wilhelm-Stahl-Allee 2, 18196, Dummerstorf, Germany
| | - Eduard Murani
- Research Institute for Farm Animal Biology (FBN), Institute for Genome Biology, Wilhelm-Stahl-Allee 2, 18196, Dummerstorf, Germany
| | - Klaus Wimmers
- Research Institute for Farm Animal Biology (FBN), Institute for Genome Biology, Wilhelm-Stahl-Allee 2, 18196, Dummerstorf, Germany.,University Rostock, Faculty of Agricultural and Environmental Sciences, 18059, Rostock, Germany
| | - Siriluck Ponsuksili
- Research Institute for Farm Animal Biology (FBN), Institute for Genome Biology, Wilhelm-Stahl-Allee 2, 18196, Dummerstorf, Germany.
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10
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Arjun McKinney A, Petrova R, Panagiotakos G. Calcium and activity-dependent signaling in the developing cerebral cortex. Development 2022; 149:dev198853. [PMID: 36102617 PMCID: PMC9578689 DOI: 10.1242/dev.198853] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022]
Abstract
Calcium influx can be stimulated by various intra- and extracellular signals to set coordinated gene expression programs into motion. As such, the precise regulation of intracellular calcium represents a nexus between environmental cues and intrinsic genetic programs. Mounting genetic evidence points to a role for the deregulation of intracellular calcium signaling in neuropsychiatric disorders of developmental origin. These findings have prompted renewed enthusiasm for understanding the roles of calcium during normal and dysfunctional prenatal development. In this Review, we describe the fundamental mechanisms through which calcium is spatiotemporally regulated and directs early neurodevelopmental events. We also discuss unanswered questions about intracellular calcium regulation during the emergence of neurodevelopmental disease, and provide evidence that disruption of cell-specific calcium homeostasis and/or redeployment of developmental calcium signaling mechanisms may contribute to adult neurological disorders. We propose that understanding the normal developmental events that build the nervous system will rely on gaining insights into cell type-specific calcium signaling mechanisms. Such an understanding will enable therapeutic strategies targeting calcium-dependent mechanisms to mitigate disease.
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Affiliation(s)
- Arpana Arjun McKinney
- Graduate Program in Developmental and Stem Cell Biology, University of California, San Francisco, CA 94143, USA
- Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, CA 94143, USA
- Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94143, USA
- Kavli Institute for Fundamental Neuroscience, University of California, San Francisco, CA 94143, USA
| | - Ralitsa Petrova
- Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, CA 94143, USA
- Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94143, USA
- Kavli Institute for Fundamental Neuroscience, University of California, San Francisco, CA 94143, USA
| | - Georgia Panagiotakos
- Graduate Program in Developmental and Stem Cell Biology, University of California, San Francisco, CA 94143, USA
- Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, CA 94143, USA
- Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94143, USA
- Kavli Institute for Fundamental Neuroscience, University of California, San Francisco, CA 94143, USA
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11
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Qian T, Qiao P, Lu Y, Wang H. Transcription factor SS18L1 regulates the proliferation, migration and differentiation of Schwann cells in peripheral nerve injury. Front Vet Sci 2022; 9:936620. [PMID: 36046506 PMCID: PMC9420995 DOI: 10.3389/fvets.2022.936620] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Accepted: 07/27/2022] [Indexed: 11/30/2022] Open
Abstract
Transcription factors bind to specific DNA sequences, modulate the transcription of target genes, and regulate various biological processes, including peripheral nerve regeneration. Our previous analysis showed that SS18L1, a gene encoding the transcription factor SS18-like protein 1, was differentially expressed in the distal sciatic nerve stumps after rat sciatic nerve transection injury, but its effect on peripheral nerve injury has not been reported. In the current study, we isolated and cultured primary Schwann cells, and examined the role of SS18L1 for the biological functions of the cells. Depletion of SS18L1 by siRNA in Schwann cells enhanced cell proliferation and inhibited cell migration, as determined by EdU assay and transwell migration assay, respectively. In addition, silencing of SS18L1 inhibited Schwann cell differentiation induced by HRG and cAMP. Bioinformatics analyses revealed an interaction network of SS18L1, including DF2, SMARCD1, SMARCA4, and SMARCE1, which may be implicated in the regulatory functions of SS18L1 on the proliferation, migration and differentiation of Schwann cells. In conclusion, our results revealed a temporal expression profile of SS18L1 in peripheral nerve injury and its potential roles during the process of nerve recovery.
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Affiliation(s)
- Tianmei Qian
- Suzhou Medical College of Soochow University, Suzhou, China
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong, China
| | - Pingping Qiao
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong, China
| | - Yingnan Lu
- School of Overseas Education, Changzhou University, Changzhou, China
| | - Hongkui Wang
- Suzhou Medical College of Soochow University, Suzhou, China
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong, China
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12
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Lins ÉM, Oliveira NCM, Reis O, Ferrasa A, Herai R, Muotri AR, Massirer KB, Bengtson MH. Genome-wide translation control analysis of developing human neurons. Mol Brain 2022; 15:55. [PMID: 35706057 PMCID: PMC9199153 DOI: 10.1186/s13041-022-00940-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2022] [Accepted: 05/29/2022] [Indexed: 11/25/2022] Open
Abstract
During neuronal differentiation, neuroprogenitor cells become polarized, change shape, extend axons, and form complex dendritic trees. While growing, axons are guided by molecular cues to their final destination, where they establish synaptic connections with other neuronal cells. Several layers of regulation are integrated to control neuronal development properly. Although control of mRNA translation plays an essential role in mammalian gene expression, how it contributes temporarily to the modulation of later stages of neuronal differentiation remains poorly understood. Here, we investigated how translation control affects pathways and processes essential for neuronal maturation, using H9-derived human neuro progenitor cells differentiated into neurons as a model. Through Ribosome Profiling (Riboseq) combined with RNA sequencing (RNAseq) analysis, we found that translation control regulates the expression of critical hub genes. Fundamental synaptic vesicle secretion genes belonging to SNARE complex, Rab family members, and vesicle acidification ATPases are strongly translationally regulated in developing neurons. Translational control also participates in neuronal metabolism modulation, particularly affecting genes involved in the TCA cycle and glutamate synthesis/catabolism. Importantly, we found translation regulation of several critical genes with fundamental roles regulating actin and microtubule cytoskeleton pathways, critical to neurite generation, spine formation, axon guidance, and circuit formation. Our results show that translational control dynamically integrates important signals in neurons, regulating several aspects of its development and biology.
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Affiliation(s)
- Érico Moreto Lins
- Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas-UNICAMP, Campinas, SP, 13083-970, Brazil.,Graduate Program in Genetics and Molecular Biology (PGBM), UNICAMP, Campinas, SP, 13083-886, Brazil
| | - Natássia Cristina Martins Oliveira
- Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas-UNICAMP, Campinas, SP, 13083-970, Brazil.,Center of Medicinal Chemistry-CQMED, Structural Genomics Consortium-SGC, University of Campinas-UNICAMP, Campinas, SP, 13083-886, Brazil
| | - Osvaldo Reis
- Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas-UNICAMP, Campinas, SP, 13083-970, Brazil
| | - Adriano Ferrasa
- School of Medicine, Graduate Program in Health Sciences, Pontifícia Universidade Católica do Paraná, Curitiba, PR, 80215-901, Brazil.,Department of Computer Science, State University of Ponta Grossa-UEPG, Ponta Grossa, PR, 84030-900, Brazil
| | - Roberto Herai
- School of Medicine, Graduate Program in Health Sciences, Pontifícia Universidade Católica do Paraná, Curitiba, PR, 80215-901, Brazil
| | - Alysson R Muotri
- Department of Pediatrics and Cellular and Molecular Medicine, School of Medicine, UC San Diego, La Jolla, CA, 92037, Brazil
| | - Katlin Brauer Massirer
- Center for Molecular Biology and Genetic Engineering-CBMEG, University of Campinas-UNICAMP, Campinas, SP, 13083-875, Brazil.,Center of Medicinal Chemistry-CQMED, Structural Genomics Consortium-SGC, University of Campinas-UNICAMP, Campinas, SP, 13083-886, Brazil
| | - Mário Henrique Bengtson
- Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas-UNICAMP, Campinas, SP, 13083-970, Brazil. .,Center of Medicinal Chemistry-CQMED, Structural Genomics Consortium-SGC, University of Campinas-UNICAMP, Campinas, SP, 13083-886, Brazil.
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13
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Todd TW, Petrucelli L. Modelling amyotrophic lateral sclerosis in rodents. Nat Rev Neurosci 2022; 23:231-251. [PMID: 35260846 DOI: 10.1038/s41583-022-00564-x] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/27/2022] [Indexed: 12/11/2022]
Abstract
The efficient study of human disease requires the proper tools, one of the most crucial of which is an accurate animal model that faithfully recapitulates the human condition. The study of amyotrophic lateral sclerosis (ALS) is no exception. Although the majority of ALS cases are considered sporadic, most animal models of this disease rely on genetic mutations identified in familial cases. Over the past decade, the number of genes associated with ALS has risen dramatically and, with each new genetic variant, there is a drive to develop associated animal models. Rodent models are of particular importance as they allow for the study of ALS in the context of a living mammal with a comparable CNS. Such models not only help to verify the pathogenicity of novel mutations but also provide critical insight into disease mechanisms and are crucial for the testing of new therapeutics. In this Review, we aim to summarize the full spectrum of ALS rodent models developed to date.
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Affiliation(s)
- Tiffany W Todd
- Department of Neuroscience, Mayo Clinic Jacksonville, Jacksonville, FL, USA
| | - Leonard Petrucelli
- Department of Neuroscience, Mayo Clinic Jacksonville, Jacksonville, FL, USA.
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14
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Rowland ME, Jajarmi JM, Osborne TSM, Ciernia AV. Insights Into the Emerging Role of Baf53b in Autism Spectrum Disorder. Front Mol Neurosci 2022; 15:805158. [PMID: 35185468 PMCID: PMC8852769 DOI: 10.3389/fnmol.2022.805158] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Accepted: 01/11/2022] [Indexed: 12/15/2022] Open
Abstract
Accurate and precise regulation of gene expression is necessary to ensure proper brain development and plasticity across the lifespan. As an ATP-dependent chromatin-remodeling complex, the BAF (Brg1 Associated Factor) complex can alter histone-DNA interactions, facilitating dynamic changes in gene expression by controlling DNA accessibility to the transcriptional machinery. Mutations in 12 of the potential 29 subunit genes that compose the BAF nucleosome remodeling complex have been identified in several developmental disorders including Autism spectrum disorders (ASD) and intellectual disability. A novel, neuronal version of BAF (nBAF) has emerged as promising candidate in the development of ASD as its expression is tied to neuron differentiation and it’s hypothesized to coordinate expression of synaptic genes across brain development. Recently, mutations in BAF53B, one of the neuron specific subunits of the nBAF complex, have been identified in patients with ASD and Developmental and epileptic encephalopathy-76 (DEE76), indicating BAF53B is essential for proper brain development. Recent work in cultured neurons derived from patients with BAF53B mutations suggests links between loss of nBAF function and neuronal dendritic spine formation. Deletion of one or both copies of mouse Baf53b disrupts dendritic spine development, alters actin dynamics and results in fewer synapses in vitro. In the mouse, heterozygous loss of Baf53b severely impacts synaptic plasticity and long-term memory that is reversible with reintroduction of Baf53b or manipulations of the synaptic plasticity machinery. Furthermore, surviving Baf53b-null mice display ASD-related behaviors, including social impairments and repetitive behaviors. This review summarizes the emerging evidence linking deleterious variants of BAF53B identified in human neurodevelopmental disorders to abnormal transcriptional regulation that produces aberrant synapse development and behavior.
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15
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Identification of novel SSX1 fusions in synovial sarcoma. Mod Pathol 2022; 35:228-239. [PMID: 34504309 DOI: 10.1038/s41379-021-00910-x] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2021] [Revised: 08/13/2021] [Accepted: 08/15/2021] [Indexed: 12/28/2022]
Abstract
Synovial sarcoma is characterized by variable epithelial differentiation and specific SS18-SSX gene fusions. The diagnosis is primarily based on phenotype, but fusion gene detection is increasingly being considered indispensable, with SS18 break-apart fluorescence in situ hybridization (FISH) being favored in many laboratories. However, SS18 FISH assay produces negative or atypical results in a minority of cases, leaving uncertainties in diagnosis and management. Here, we analyzed this challenging subset of SS18 FISH-negative/atypical synovial sarcoma using RNA sequencing and monoclonal antibodies that recognize SS18-SSX and the SSX C-terminus. Among 99 synovial sarcoma cases that were previously subjected to SS18 break-apart FISH, eight cases were reported as negative and three cases were indeterminate, owing to atypical signal patterns. Three of these 11 tumors (two monophasic and one biphasic) harbored novel EWSR1-SSX1 fusions, were negative for SS18-SSX staining, and were positive for SSX C-terminus staining. One monophasic tumor harbored a novel MN1-SSX1 fusion, and showed negative SS18-SSX expression and positive SSX C-terminus staining. Another monophasic tumor carried an SS18L1-SSX1 fusion, and was weakly positive for SS18-SSX, while SMARCB1 expression was reduced. The presence of these novel and/or rare fusions was confirmed using RT-PCR and Sanger sequencing. EWSR1-SSX1 was further validated by EWSR1 FISH assay. The remaining six tumors (five monophasic and one biphasic) showed strong SS18-SSX expression, and RNA sequencing successfully performed in three cases identified canonical SS18-SSX2 fusions. Based on a DNA methylation-based unsupervised clustering, the tumors with EWSR1-SSX1 and SS18L1-SSX1 clustered with synovial sarcoma, while the MN1-SSX1-positive tumor was not co-clustered despite classic histology and immunoprofile. In summary, we discovered novel and rare SSX1 fusions to non-SS18 genes in synovial sarcoma. The expanded genetic landscape carries significant diagnostic implications and advances our understanding of the oncogenic mechanism.
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16
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Neurobiology of ARID1B haploinsufficiency related to neurodevelopmental and psychiatric disorders. Mol Psychiatry 2022; 27:476-489. [PMID: 33686214 PMCID: PMC8423853 DOI: 10.1038/s41380-021-01060-x] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2020] [Revised: 02/04/2021] [Accepted: 02/18/2021] [Indexed: 01/31/2023]
Abstract
ARID1B haploinsufficiency is a frequent cause of intellectual disability (ID) and autism spectrum disorder (ASD), and also leads to emotional disturbances. In this review, we examine past and present clinical and preclinical research into the neurobiological function of ARID1B. The presentation of ARID1B-related disorders (ARID1B-RD) is highly heterogeneous, including varying degrees of ID, ASD, and physical features. Recent research includes the development of suitable clinical readiness assessments for the treatment of ARID1B-RD, as well as similar neurodevelopmental disorders. Recently developed mouse models of Arid1b haploinsufficiency successfully mirror many of the behavioral phenotypes of ASD and ID. These animal models have helped to solidify the molecular mechanisms by which ARID1B regulates brain development and function, including epigenetic regulation of the Pvalb gene and promotion of Wnt/β-catenin signaling in neural progenitors in the ventral telencephalon. Finally, preclinical studies have identified the use of a positive allosteric modulator of the GABAA receptor as an effective treatment for some Arid1b haploinsufficiency-related behavioral phenotypes, and there is potential for the refinement of this therapy in order to translate it into clinical use.
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17
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Kartamihardja AAP, Ariyani W, Hanaoka H, Taketomi-Takahashi A, Koibuchi N, Tsushima Y. The Role of Ferrous Ion in the Effect of the Gadolinium-Based Contrast Agents (GBCA) on the Purkinje Cells Arborization: An In Vitro Study. Diagnostics (Basel) 2021; 11:2310. [PMID: 34943547 PMCID: PMC8699861 DOI: 10.3390/diagnostics11122310] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Revised: 11/23/2021] [Accepted: 12/06/2021] [Indexed: 11/27/2022] Open
Abstract
Gadolinium deposition in the brain has been observed in areas rich in iron, such as the dentate nucleus of the cerebellum. We investigated the role of Fe2+ in the effect of gadolinium-based contrast agents (GBCA) on thyroid hormone-mediated Purkinje cell dendritogenesis in a cerebellar primary culture. The study comprises the control group, Fe2+ group, GBCA groups (gadopentetate group or gadobutrol group), and GBCA+Fe2+ groups. Immunocytochemistry was performed with an anti-calbindin-28K (anti-CaBP28k) antibody, and the nucleus was stained with 4',6-diamidino-2-phenylindole (DAPI). The number of Purkinje cells and their arborization were evaluated with an analysis of variance with a post-hoc test. The number of Purkinje cells was similar to the control groups among all treated groups. There were no significant differences in dendrite arborization between the Fe2+ group and the control groups. The dendrite arborization was augmented in the gadopentetate and the gadobutrol groups when compared to the control group (p < 0.01, respectively). Fe2+ significantly increased the effect of gadopentetate on dendrite arborization (p < 0.01) but did not increase the effect of gadobutrol. These findings suggested that the chelate thermodynamic stability and Fe2+ may play important roles in attenuating the effect of GBCAs on the thyroid hormone-mediated dendritogenesis of Purkinje cells in in vitro settings.
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Affiliation(s)
- Achmad Adhipatria Perayabangsa Kartamihardja
- Department of Diagnostic Radiology and Nuclear Medicine, Gunma University Graduate School of Medicine, Maebashi 371-8511, Japan; (A.A.P.K.); (A.T.-T.)
- Department of Nuclear Medicine and Molecular Imaging, Universitas Padjajaran, Bandung 40161, Indonesia
| | - Winda Ariyani
- Department of Integrative Physiology, Gunma University Graduate School of Medicine, Maebashi 371-8511, Japan; (W.A.); (N.K.)
| | - Hirofumi Hanaoka
- Department of Bioimaging and Information Analysis, Gunma University Graduate School of Medicine, Maebashi 371-8511, Japan;
| | - Ayako Taketomi-Takahashi
- Department of Diagnostic Radiology and Nuclear Medicine, Gunma University Graduate School of Medicine, Maebashi 371-8511, Japan; (A.A.P.K.); (A.T.-T.)
| | - Noriyuki Koibuchi
- Department of Integrative Physiology, Gunma University Graduate School of Medicine, Maebashi 371-8511, Japan; (W.A.); (N.K.)
| | - Yoshito Tsushima
- Department of Diagnostic Radiology and Nuclear Medicine, Gunma University Graduate School of Medicine, Maebashi 371-8511, Japan; (A.A.P.K.); (A.T.-T.)
- Division of Integrated Oncology Research, Gunma Initiative for Advanced Research, Gunma University Graduate School of Medicine, Maebashi 371-8511, Japan
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18
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Connecting the Neurobiology of Developmental Brain Injury: Neuronal Arborisation as a Regulator of Dysfunction and Potential Therapeutic Target. Int J Mol Sci 2021; 22:ijms22158220. [PMID: 34360985 PMCID: PMC8348801 DOI: 10.3390/ijms22158220] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Revised: 07/23/2021] [Accepted: 07/28/2021] [Indexed: 11/17/2022] Open
Abstract
Neurodevelopmental disorders can derive from a complex combination of genetic variation and environmental pressures on key developmental processes. Despite this complex aetiology, and the equally complex array of syndromes and conditions diagnosed under the heading of neurodevelopmental disorder, there are parallels in the neuropathology of these conditions that suggest overlapping mechanisms of cellular injury and dysfunction. Neuronal arborisation is a process of dendrite and axon extension that is essential for the connectivity between neurons that underlies normal brain function. Disrupted arborisation and synapse formation are commonly reported in neurodevelopmental disorders. Here, we summarise the evidence for disrupted neuronal arborisation in these conditions, focusing primarily on the cortex and hippocampus. In addition, we explore the developmentally specific mechanisms by which neuronal arborisation is regulated. Finally, we discuss key regulators of neuronal arborisation that could link to neurodevelopmental disease and the potential for pharmacological modification of arborisation and the formation of synaptic connections that may provide therapeutic benefit in the future.
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19
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D'Souza L, Channakkar AS, Muralidharan B. Chromatin remodelling complexes in cerebral cortex development and neurodevelopmental disorders. Neurochem Int 2021; 147:105055. [PMID: 33964373 PMCID: PMC7611358 DOI: 10.1016/j.neuint.2021.105055] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2020] [Revised: 04/11/2021] [Accepted: 04/24/2021] [Indexed: 12/19/2022]
Abstract
The diverse number of neurons in the cerebral cortex are generated during development by neural stem cells lining the ventricle, and they continue maturing postnatally. Dynamic chromatin regulation in these neural stem cells is a fundamental determinant of the emerging property of the functional neural network, and the chromatin remodellers are critical determinants of this process. Chromatin remodellers participate in several steps of this process from proliferation, differentiation, migration leading to complex network formation which forms the basis of higher-order functions of cognition and behaviour. Here we review the role of these ATP-dependent chromatin remodellers in cortical development in health and disease and highlight several key mouse mutants of the subunits of the complexes which have revealed how the remodelling mechanisms control the cortical stem cell chromatin landscape for expression of stage-specific transcripts. Consistent with their role in cortical development, several putative risk variants in the subunits of the remodelling complexes have been identified as the underlying causes of several neurodevelopmental disorders. A basic understanding of the detailed molecular mechanism of their action is key to understating how mutations in the same networks lead to disease pathologies and perhaps pave the way for therapeutic development for these complex multifactorial disorders.
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Affiliation(s)
- Leora D'Souza
- Brain Development and Disease Mechanisms, Institute for Stem Cell Science and Regenerative Medicine (inStem), Bangalore Life Science Cluster, Bangalore, India
| | - Asha S Channakkar
- Brain Development and Disease Mechanisms, Institute for Stem Cell Science and Regenerative Medicine (inStem), Bangalore Life Science Cluster, Bangalore, India
| | - Bhavana Muralidharan
- Brain Development and Disease Mechanisms, Institute for Stem Cell Science and Regenerative Medicine (inStem), Bangalore Life Science Cluster, Bangalore, India.
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20
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Su X, Huang Y, Chen R, Zhang Y, He M, Lü X. Metabolomics analysis of poly(l-lactic acid) nanofibers' performance on PC12 cell differentiation. Regen Biomater 2021; 8:rbab031. [PMID: 34168894 PMCID: PMC8218933 DOI: 10.1093/rb/rbab031] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2021] [Revised: 04/30/2021] [Accepted: 05/21/2021] [Indexed: 11/14/2022] Open
Abstract
The aim of this article is to reveal the influence of aligned/random poly(l-lactic acid) (PLLA) nanofibers on PC12 cell differentiation from the perspective of metabolic level. First, three materials-PLLA aligned nanofibers (PLLA AF), PLLA random nanofibers (PLLA RF) and PLLA films (control)-were prepared by electrospinning and spin coating. Their surface morphologies were characterized. Subsequently, the cell viability, cell morphology and neurite length of PC12 cells on the surface of the three materials were evaluated, indicating more neurites in the PLLA RF groups but the longer average neurite length in the PLLA AF groups. Next, the metabolite profiles of PC12 cells cultured on the surface of the three nanofibers after 12 h, 24 h and 36 h showed that, compared with the control, 51, 48 and 31 types of differential metabolites were detected at the three time points among the AF groups, respectively; and 56, 45 and 41 types among the RF groups, respectively. Furthermore, the bioinformatics analysis of differential metabolites identified two pathways and three metabolites critical to PC12 cell differentiation influenced by the nanofibers. In addition, the verification experiment on critical metabolites and metabolic pathways were performed. The integrative analysis combining cytology, metabolomics and bioinformatics approaches revealed that though both PLLA AF and RF were capable of stimulating the synthesis of neurotransmitters, the PLLA AF were more beneficial for PC12 cell differentiation, whereas the PLLA RF were less effective.
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Affiliation(s)
- Xiaoman Su
- State Key Laboratory of Bioelectronics, School of Biological Science and Medical Engineering, Southeast University, 2# Si Pailou, Nanjing 210096, China
| | - Yan Huang
- State Key Laboratory of Bioelectronics, School of Biological Science and Medical Engineering, Southeast University, 2# Si Pailou, Nanjing 210096, China
| | - Rong Chen
- State Key Laboratory of Bioelectronics, School of Biological Science and Medical Engineering, Southeast University, 2# Si Pailou, Nanjing 210096, China
| | - Yiwen Zhang
- Department of Research, SQ Medical Device Co., Ltd, 17# Xinghuo Road, Nanjing 211500, China
| | - Meichen He
- State Key Laboratory of Bioelectronics, School of Biological Science and Medical Engineering, Southeast University, 2# Si Pailou, Nanjing 210096, China
| | - Xiaoying Lü
- State Key Laboratory of Bioelectronics, School of Biological Science and Medical Engineering, Southeast University, 2# Si Pailou, Nanjing 210096, China.,Co-innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu Province 226019, China
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21
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Braun SMG, Petrova R, Tang J, Krokhotin A, Miller EL, Tang Y, Panagiotakos G, Crabtree GR. BAF subunit switching regulates chromatin accessibility to control cell cycle exit in the developing mammalian cortex. Genes Dev 2021; 35:335-353. [PMID: 33602870 PMCID: PMC7919417 DOI: 10.1101/gad.342345.120] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2020] [Accepted: 01/08/2021] [Indexed: 12/28/2022]
Abstract
mSWI/SNF or BAF chromatin regulatory complexes are dosage-sensitive regulators of human neural development frequently mutated in autism spectrum disorders and intellectual disability. Cell cycle exit and differentiation of neural stem/progenitor cells is accompanied by BAF subunit switching to generate neuron-specific nBAF complexes. We manipulated the timing of BAF subunit exchange in vivo and found that early loss of the npBAF subunit BAF53a stalls the cell cycle to disrupt neurogenesis. Loss of BAF53a results in decreased chromatin accessibility at specific neural transcription factor binding sites, including the pioneer factors SOX2 and ASCL1, due to Polycomb accumulation. This results in repression of cell cycle genes, thereby blocking cell cycle progression and differentiation. Cell cycle block upon Baf53a deletion could be rescued by premature expression of the nBAF subunit BAF53b but not by other major drivers of proliferation or differentiation. WNT, EGF, bFGF, SOX2, c-MYC, or PAX6 all fail to maintain proliferation in the absence of BAF53a, highlighting a novel mechanism underlying neural progenitor cell cycle exit in the continued presence of extrinsic proliferative cues.
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Affiliation(s)
- Simon M G Braun
- Howard Hughes Medical Institute, Stanford University, Stanford, California 94305, USA
- Department of Developmental Biology, Stanford University, California 94305, USA
- Department of Pathology, Stanford University, California 94305, USA
- Department of Genetic Medicine and Development, Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland
| | - Ralitsa Petrova
- Department of Biochemistry and Biophysics, University of California at San Francisco, San Francisco, California 94143, USA
- Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California at San Francisco, San Francisco, California 94143, USA
- Kavli Institute for Fundamental Neuroscience, University of California at San Francisco, San Francisco, California 94143, USA
| | - Jiong Tang
- Howard Hughes Medical Institute, Stanford University, Stanford, California 94305, USA
- Department of Developmental Biology, Stanford University, California 94305, USA
- Department of Pathology, Stanford University, California 94305, USA
- Singapore Bioimaging Consortium, Agency for Science Technology and Research (A*STAR), Singapore 138667, Singapore
| | - Andrey Krokhotin
- Howard Hughes Medical Institute, Stanford University, Stanford, California 94305, USA
- Department of Developmental Biology, Stanford University, California 94305, USA
- Department of Pathology, Stanford University, California 94305, USA
| | - Erik L Miller
- Howard Hughes Medical Institute, Stanford University, Stanford, California 94305, USA
- Department of Developmental Biology, Stanford University, California 94305, USA
- Department of Pathology, Stanford University, California 94305, USA
| | - Yitai Tang
- Department of Pathology, Stanford University, California 94305, USA
| | - Georgia Panagiotakos
- Department of Biochemistry and Biophysics, University of California at San Francisco, San Francisco, California 94143, USA
- Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California at San Francisco, San Francisco, California 94143, USA
- Kavli Institute for Fundamental Neuroscience, University of California at San Francisco, San Francisco, California 94143, USA
| | - Gerald R Crabtree
- Howard Hughes Medical Institute, Stanford University, Stanford, California 94305, USA
- Department of Developmental Biology, Stanford University, California 94305, USA
- Department of Pathology, Stanford University, California 94305, USA
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22
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Abstract
Neurons develop dendritic morphologies that bear cell type-specific features in dendritic field size and geometry, branch placement and density, and the types and distributions of synaptic contacts. Dendritic patterns influence the types and numbers of inputs a neuron receives, and the ways in which neural information is processed and transmitted in the circuitry. Even subtle alterations in dendritic structures can have profound consequences on neuronal function and are implicated in neurodevelopmental disorders. In this chapter, I review how growing dendrites acquire their exquisite patterns by drawing examples from diverse neuronal cell types in vertebrate and invertebrate model systems. Dendrite morphogenesis is shaped by intrinsic and extrinsic factors such as transcriptional regulators, guidance and adhesion molecules, neighboring cells and synaptic partners. I discuss molecular mechanisms that regulate dendrite morphogenesis with a focus on five aspects of dendrite patterning: (1) Dendritic cytoskeleton and cellular machineries that build the arbor; (2) Gene regulatory mechanisms; (3) Afferent cues that regulate dendritic arbor growth; (4) Space-filling strategies that optimize dendritic coverage; and (5) Molecular cues that specify dendrite wiring. Cell type-specific implementation of these patterning mechanisms produces the diversity of dendrite morphologies that wire the nervous system.
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23
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Nourbakhsh K, Yadav S. Kinase Signaling in Dendritic Development and Disease. Front Cell Neurosci 2021; 15:624648. [PMID: 33642997 PMCID: PMC7902504 DOI: 10.3389/fncel.2021.624648] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2020] [Accepted: 01/06/2021] [Indexed: 01/19/2023] Open
Abstract
Dendrites undergo extensive growth and remodeling during their lifetime. Specification of neurites into dendrites is followed by their arborization, maturation, and functional integration into synaptic networks. Each of these distinct developmental processes is spatially and temporally controlled in an exquisite fashion. Protein kinases through their highly specific substrate phosphorylation regulate dendritic growth and plasticity. Perturbation of kinase function results in aberrant dendritic growth and synaptic function. Not surprisingly, kinase dysfunction is strongly associated with neurodevelopmental and psychiatric disorders. Herein, we review, (a) key kinase pathways that regulate dendrite structure, function and plasticity, (b) how aberrant kinase signaling contributes to dendritic dysfunction in neurological disorders and (c) emergent technologies that can be applied to dissect the role of protein kinases in dendritic structure and function.
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Affiliation(s)
| | - Smita Yadav
- Department of Pharmacology, University of Washington, Seattle, WA, United States
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24
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Quach TT, Stratton HJ, Khanna R, Kolattukudy PE, Honnorat J, Meyer K, Duchemin AM. Intellectual disability: dendritic anomalies and emerging genetic perspectives. Acta Neuropathol 2021; 141:139-158. [PMID: 33226471 PMCID: PMC7855540 DOI: 10.1007/s00401-020-02244-5] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2020] [Revised: 11/04/2020] [Accepted: 11/05/2020] [Indexed: 12/12/2022]
Abstract
Intellectual disability (ID) corresponds to several neurodevelopmental disorders of heterogeneous origin in which cognitive deficits are commonly associated with abnormalities of dendrites and dendritic spines. These histological changes in the brain serve as a proxy for underlying deficits in neuronal network connectivity, mostly a result of genetic factors. Historically, chromosomal abnormalities have been reported by conventional karyotyping, targeted fluorescence in situ hybridization (FISH), and chromosomal microarray analysis. More recently, cytogenomic mapping, whole-exome sequencing, and bioinformatic mining have led to the identification of novel candidate genes, including genes involved in neuritogenesis, dendrite maintenance, and synaptic plasticity. Greater understanding of the roles of these putative ID genes and their functional interactions might boost investigations into determining the plausible link between cellular and behavioral alterations as well as the mechanisms contributing to the cognitive impairment observed in ID. Genetic data combined with histological abnormalities, clinical presentation, and transgenic animal models provide support for the primacy of dysregulation in dendrite structure and function as the basis for the cognitive deficits observed in ID. In this review, we highlight the importance of dendrite pathophysiology in the etiologies of four prototypical ID syndromes, namely Down Syndrome (DS), Rett Syndrome (RTT), Digeorge Syndrome (DGS) and Fragile X Syndrome (FXS). Clinical characteristics of ID have also been reported in individuals with deletions in the long arm of chromosome 10 (the q26.2/q26.3), a region containing the gene for the collapsin response mediator protein 3 (CRMP3), also known as dihydropyrimidinase-related protein-4 (DRP-4, DPYSL4), which is involved in dendritogenesis. Following a discussion of clinical and genetic findings in these syndromes and their preclinical animal models, we lionize CRMP3/DPYSL4 as a novel candidate gene for ID that may be ripe for therapeutic intervention.
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Affiliation(s)
- Tam T Quach
- Institute for Behavioral Medicine Research, Wexner Medical Center, The Ohio State University, Columbus, OH, 43210, USA
- INSERM U1217/CNRS, UMR5310, Université de Lyon, Université Claude Bernard Lyon 1, Lyon, France
| | | | - Rajesh Khanna
- Department of Pharmacology, University of Arizona, Tucson, AZ, 85724, USA
| | | | - Jérome Honnorat
- INSERM U1217/CNRS, UMR5310, Université de Lyon, Université Claude Bernard Lyon 1, Lyon, France
- French Reference Center on Paraneoplastic Neurological Syndromes and Autoimmune Encephalitis, Hospices Civils de Lyon, Lyon, France
- SynatAc Team, Institut NeuroMyoGène, Lyon, France
| | - Kathrin Meyer
- The Research Institute of Nationwide Children Hospital, Columbus, OH, 43205, USA
- Department of Pediatric, The Ohio State University, Columbus, OH, 43210, USA
| | - Anne-Marie Duchemin
- Department of Psychiatry and Behavioral Health, The Ohio State University, Columbus, OH, 43210, USA.
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25
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Du A, Li L, Jiao Z, Zhu G, Peng T, Li H. Protein expression pattern of calcium-responsive transactivator in early postnatal and adult testes. Histochem Cell Biol 2021; 155:491-502. [PMID: 33398438 PMCID: PMC8062385 DOI: 10.1007/s00418-020-01942-1] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/09/2020] [Indexed: 11/27/2022]
Abstract
Calcium-responsive transactivator (CREST), a nuclear protein highly expressed in postmitotic neurons, is involved in the regulation of cell cycle, differentiation and dendritic development of neuronal cells. Its mRNA has been detected in the testis of adult rat, whilst its protein expression and distribution pattern in the testis remain to be elucidated. In this study, we examined the distribution of CREST in the adult testes of both rats and human as well as the expression pattern of CREST in the testes of postnatal developing rats. In the adult testes of both human and rats, immunohistochemical analysis revealed that CREST was selectively distributed in the mature Sertoli cells but not in the spermatogenic cells. In the testes of postnatal developmental rats, CREST was expressed not only in Sertoli cells but also in the gonocytes and spermatogenic cells at the initial stage of spermatogenic cell differentiation. CREST immunoreactivity continued to increase in Sertoli cells during differentiation, reaching its peak in adulthood. However, CREST immunostaining intensity dramatically decreased as the spermatogenic cells differentiate, disappearing in the post-differentiation stage. Furthermore, Brg1 and p300, two CREST-interacting proteins ubiquitously expressed in the body, are found to be colocalized with CREST in the spermatogenic epithelial cells including Sertoli cells. The unique expression pattern of CREST in developing testis suggests that CREST might play regulatory roles in the differentiation of spermatogenic epithelial cells. The Sertoli cell-specific expression of CREST in the adulthood hints that CREST might be a novel biomarker for the mature Sertoli cells.
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Affiliation(s)
- Ana Du
- Department of Histology and Embryology, School of Basic Medical Sciences, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Li Li
- School of Biomedical Sciences, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Zhaoshuang Jiao
- Department of Histology and Embryology, School of Basic Medical Sciences, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Gaochun Zhu
- Department of Anatomy, School of Basic Medicine, Nanchang University, Nanchang, 330006, China
| | - Ting Peng
- Department of Histology and Embryology, School of Basic Medical Sciences, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
| | - He Li
- Department of Histology and Embryology, School of Basic Medical Sciences, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China. .,Hubei Key Laboratory of Embryonic Stem Cell Research, Hubei University of Medicine, Shiyan, 442000, China.
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26
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Smolen P, Wood MA, Baxter DA, Byrne JH. Modeling suggests combined-drug treatments for disorders impairing synaptic plasticity via shared signaling pathways. J Comput Neurosci 2020; 49:37-56. [PMID: 33175283 DOI: 10.1007/s10827-020-00771-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2019] [Revised: 08/27/2020] [Accepted: 10/19/2020] [Indexed: 12/15/2022]
Abstract
Genetic disorders such as Rubinstein-Taybi syndrome (RTS) and Coffin-Lowry syndrome (CLS) cause lifelong cognitive disability, including deficits in learning and memory. Can pharmacological therapies be suggested that improve learning and memory in these disorders? To address this question, we simulated drug effects within a computational model describing induction of late long-term potentiation (L-LTP). Biochemical pathways impaired in these and other disorders converge on a common target, histone acetylation by acetyltransferases such as CREB binding protein (CBP), which facilitates gene induction necessary for L-LTP. We focused on four drug classes: tropomyosin receptor kinase B (TrkB) agonists, cAMP phosphodiesterase inhibitors, histone deacetylase inhibitors, and ampakines. Simulations suggested each drug type alone may rescue deficits in L-LTP. A potential disadvantage, however, was the necessity of simulating strong drug effects (high doses), which could produce adverse side effects. Thus, we investigated the effects of six drug pairs among the four classes described above. These combination treatments normalized impaired L-LTP with substantially smaller individual drug 'doses'. In addition three of these combinations, a TrkB agonist paired with an ampakine and a cAMP phosphodiesterase inhibitor paired with a TrkB agonist or an ampakine, exhibited strong synergism in L-LTP rescue. Therefore, we suggest these drug combinations are promising candidates for further empirical studies in animal models of genetic disorders that impair histone acetylation, L-LTP, and learning.
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Affiliation(s)
- Paul Smolen
- Department of Neurobiology and Anatomy, W.M. Keck Center for the Neurobiology of Learning and Memory, McGovern Medical School of the University of Texas Health Science Center at Houston, Houston, TX, 77030, USA.
| | - Marcelo A Wood
- Department of Neurobiology and Behavior, University of California Irvine, Irvine, CA, 92697, USA
| | - Douglas A Baxter
- Department of Neurobiology and Anatomy, W.M. Keck Center for the Neurobiology of Learning and Memory, McGovern Medical School of the University of Texas Health Science Center at Houston, Houston, TX, 77030, USA
| | - John H Byrne
- Department of Neurobiology and Anatomy, W.M. Keck Center for the Neurobiology of Learning and Memory, McGovern Medical School of the University of Texas Health Science Center at Houston, Houston, TX, 77030, USA
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López AJ, Hecking JK, White AO. The Emerging Role of ATP-Dependent Chromatin Remodeling in Memory and Substance Use Disorders. Int J Mol Sci 2020; 21:E6816. [PMID: 32957495 PMCID: PMC7555352 DOI: 10.3390/ijms21186816] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2020] [Revised: 09/14/2020] [Accepted: 09/14/2020] [Indexed: 02/06/2023] Open
Abstract
Long-term memory formation requires coordinated regulation of gene expression and persistent changes in cell function. For decades, research has implicated histone modifications in regulating chromatin compaction necessary for experience-dependent changes to gene expression and cell function during memory formation. Recent evidence suggests that another epigenetic mechanism, ATP-dependent chromatin remodeling, works in concert with the histone-modifying enzymes to produce large-scale changes to chromatin structure. This review examines how histone-modifying enzymes and chromatin remodelers restructure chromatin to facilitate memory formation. We highlight the emerging evidence implicating ATP-dependent chromatin remodeling as an essential mechanism that mediates activity-dependent gene expression, plasticity, and cell function in developing and adult brains. Finally, we discuss how studies that target chromatin remodelers have expanded our understanding of the role that these complexes play in substance use disorders.
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Affiliation(s)
- Alberto J. López
- Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA;
| | - Julia K. Hecking
- Department of Biological Sciences, Mount Holyoke College, South Hadley, MA 01075, USA;
| | - André O. White
- Department of Biological Sciences, Mount Holyoke College, South Hadley, MA 01075, USA;
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Runge K, Cardoso C, de Chevigny A. Dendritic Spine Plasticity: Function and Mechanisms. Front Synaptic Neurosci 2020. [DOI: 10.3389/fnsyn.2020.00036
expr 823669561 + 872784217] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/16/2023] Open
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29
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Runge K, Cardoso C, de Chevigny A. Dendritic Spine Plasticity: Function and Mechanisms. Front Synaptic Neurosci 2020; 12:36. [PMID: 32982715 PMCID: PMC7484486 DOI: 10.3389/fnsyn.2020.00036] [Citation(s) in RCA: 125] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Accepted: 07/28/2020] [Indexed: 12/12/2022] Open
Abstract
Dendritic spines are small protrusions studding neuronal dendrites, first described in 1888 by Ramón y Cajal using his famous Golgi stainings. Around 50 years later the advance of electron microscopy (EM) confirmed Cajal's intuition that spines constitute the postsynaptic site of most excitatory synapses in the mammalian brain. The finding that spine density decreases between young and adult ages in fixed tissues suggested that spines are dynamic. It is only a decade ago that two-photon microscopy (TPM) has unambiguously proven the dynamic nature of spines, through the repeated imaging of single spines in live animals. Spine dynamics comprise formation, disappearance, and stabilization of spines and are modulated by neuronal activity and developmental age. Here, we review several emerging concepts in the field that start to answer the following key questions: What are the external signals triggering spine dynamics and the molecular mechanisms involved? What is, in return, the role of spine dynamics in circuit-rewiring, learning, and neuropsychiatric disorders?
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Affiliation(s)
- Karen Runge
- Institut de Neurobiologie de la Méditerranée (INMED) INSERM U1249, Aix-Marseille University, Marseille, France
| | - Carlos Cardoso
- Institut de Neurobiologie de la Méditerranée (INMED) INSERM U1249, Aix-Marseille University, Marseille, France
| | - Antoine de Chevigny
- Institut de Neurobiologie de la Méditerranée (INMED) INSERM U1249, Aix-Marseille University, Marseille, France
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30
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Bhaskar S, Gowda J, Prasanna J, Kumar A. Does altering proteasomal activity and trafficking reduce the arborization mediated specific vulnerability of SNpc dopaminergic neurons of Parkinson's disease? Med Hypotheses 2020; 143:110062. [PMID: 32652429 DOI: 10.1016/j.mehy.2020.110062] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Accepted: 06/27/2020] [Indexed: 01/15/2023]
Abstract
Parkinson's disease (PD) is a late-onset degenerative neuronal disorder and stands second among the neurological disorders with 1% of the total world population being affected. The disease originates majorly due to compromised function of the dopaminergic (DA) neurons in the Substantia Nigra pars compacta (SNpc), but not the ventral tegmental area (VTA) region of the midbrain. The differential susceptibility for degeneration is majorly attributed to morphological, molecular, and electrophysiological heterogeneity existing in DA neurons of SNpc and VTA. Long-range axonal arborization and a higher number of synapses in SNpc DA neurons make it more vulnerable compared to VTA DA neurons. Studies have shown that a decrease in such axonal arborization places DA neurons at decreased risk in PD. The two well established underlying mechanisms are a) As arborization is an energy-demanding process, increased redistribution of mitochondria to the axonal terminals occurs to satisfy the bioenergetic requirement b) The stabilization of axon-promoting factors at the axonal tip is an essential component for enhancing the arborization process. Interfering with any of these two processes would probably alleviate the degeneration of SNpc DA neurons. To accomplish the decreased stability of arborizing factors and thereby increase the resilience of SNpc DA neurons, we hypothesize the activation of anterograde transport-dependent recruitment of proteasomes to axon terminals as one of the most favorable approaches. Understanding this putative avenue of enhancing proteasomal activity and migration to the axonal tip could provide insight into the progression of neurodegeneration in PD and possibly offer a novel therapeutic strategy.
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Affiliation(s)
- Smitha Bhaskar
- Manipal Institute of Regenerative Medicine, Manipal Academy of Higher Education, Allalsandra, Yelahanka, Bengaluru 560065, Karnataka, India
| | - Jeevan Gowda
- Manipal Institute of Regenerative Medicine, Manipal Academy of Higher Education, Allalsandra, Yelahanka, Bengaluru 560065, Karnataka, India
| | - Jyothi Prasanna
- Manipal Institute of Regenerative Medicine, Manipal Academy of Higher Education, Allalsandra, Yelahanka, Bengaluru 560065, Karnataka, India
| | - Anujith Kumar
- Manipal Institute of Regenerative Medicine, Manipal Academy of Higher Education, Allalsandra, Yelahanka, Bengaluru 560065, Karnataka, India.
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31
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Dejene EA, Li Y, Showkatian Z, Ling H, Seto E. Regulation of poly(a)-specific ribonuclease activity by reversible lysine acetylation. J Biol Chem 2020; 295:10255-10270. [PMID: 32457045 DOI: 10.1074/jbc.ra120.012552] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2020] [Revised: 05/20/2020] [Indexed: 12/26/2022] Open
Abstract
Poly(A)-specific ribonuclease (PARN) is a 3'-exoribonuclease that plays an important role in regulating the stability and maturation of RNAs. Recently, PARN has been found to regulate the maturation of the human telomerase RNA component (hTR), a noncoding RNA required for telomere elongation. Specifically, PARN cleaves the 3'-end of immature, polyadenylated hTR to form the mature, nonpolyadenylated template. Despite PARN's critical role in mediating telomere maintenance, little is known about how PARN's function is regulated by post-translational modifications. In this study, using shRNA- and CRISPR/Cas9-mediated gene silencing and knockout approaches, along with 3'-exoribonuclease activity assays and additional biochemical methods, we examined whether PARN is post-translationally modified by acetylation and what effect acetylation has on PARN's activity. We found PARN is primarily acetylated by the acetyltransferase p300 at Lys-566 and deacetylated by sirtuin1 (SIRT1). We also revealed how acetylation of PARN can decrease its enzymatic activity both in vitro, using a synthetic RNA probe, and in vivo, by quantifying endogenous levels of adenylated hTR. Furthermore, we also found that SIRT1 can regulate levels of adenylated hTR through PARN. The findings of our study uncover a mechanism by which PARN acetylation and deacetylation regulate its enzymatic activity as well as levels of mature hTR. Thus, PARN's acetylation status may play a role in regulating telomere length.
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Affiliation(s)
- Eden A Dejene
- Department of Biochemistry and Molecular Medicine, George Washington University School of Medicine and Health Sciences, Washington, D.C., USA.,George Washington University Cancer Center, Washington, D.C., USA
| | - Yixuan Li
- Department of Biochemistry and Molecular Medicine, George Washington University School of Medicine and Health Sciences, Washington, D.C., USA.,George Washington University Cancer Center, Washington, D.C., USA
| | - Zahra Showkatian
- Department of Biochemistry and Molecular Medicine, George Washington University School of Medicine and Health Sciences, Washington, D.C., USA.,George Washington University Cancer Center, Washington, D.C., USA
| | - Hongbo Ling
- Department of Biochemistry and Molecular Medicine, George Washington University School of Medicine and Health Sciences, Washington, D.C., USA.,George Washington University Cancer Center, Washington, D.C., USA
| | - Edward Seto
- Department of Biochemistry and Molecular Medicine, George Washington University School of Medicine and Health Sciences, Washington, D.C., USA .,George Washington University Cancer Center, Washington, D.C., USA
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32
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Wenderski W, Wang L, Krokhotin A, Walsh JJ, Li H, Shoji H, Ghosh S, George RD, Miller EL, Elias L, Gillespie MA, Son EY, Staahl BT, Baek ST, Stanley V, Moncada C, Shipony Z, Linker SB, Marchetto MCN, Gage FH, Chen D, Sultan T, Zaki MS, Ranish JA, Miyakawa T, Luo L, Malenka RC, Crabtree GR, Gleeson JG. Loss of the neural-specific BAF subunit ACTL6B relieves repression of early response genes and causes recessive autism. Proc Natl Acad Sci U S A 2020; 117:10055-10066. [PMID: 32312822 PMCID: PMC7211998 DOI: 10.1073/pnas.1908238117] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Synaptic activity in neurons leads to the rapid activation of genes involved in mammalian behavior. ATP-dependent chromatin remodelers such as the BAF complex contribute to these responses and are generally thought to activate transcription. However, the mechanisms keeping such "early activation" genes silent have been a mystery. In the course of investigating Mendelian recessive autism, we identified six families with segregating loss-of-function mutations in the neuronal BAF (nBAF) subunit ACTL6B (originally named BAF53b). Accordingly, ACTL6B was the most significantly mutated gene in the Simons Recessive Autism Cohort. At least 14 subunits of the nBAF complex are mutated in autism, collectively making it a major contributor to autism spectrum disorder (ASD). Patient mutations destabilized ACTL6B protein in neurons and rerouted dendrites to the wrong glomerulus in the fly olfactory system. Humans and mice lacking ACTL6B showed corpus callosum hypoplasia, indicating a conserved role for ACTL6B in facilitating neural connectivity. Actl6b knockout mice on two genetic backgrounds exhibited ASD-related behaviors, including social and memory impairments, repetitive behaviors, and hyperactivity. Surprisingly, mutation of Actl6b relieved repression of early response genes including AP1 transcription factors (Fos, Fosl2, Fosb, and Junb), increased chromatin accessibility at AP1 binding sites, and transcriptional changes in late response genes associated with early response transcription factor activity. ACTL6B loss is thus an important cause of recessive ASD, with impaired neuron-specific chromatin repression indicated as a potential mechanism.
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Affiliation(s)
- Wendy Wenderski
- Department of Pathology, Stanford Medical School, Palo Alto, CA 94305
- Department of Genetics, Stanford Medical School, Palo Alto, CA 94305
- Department of Developmental Biology, Stanford Medical School, Palo Alto, CA 94305
- Howard Hughes Medical Institute, Stanford University, Palo Alto, CA 94305
| | - Lu Wang
- Department of Neuroscience, University of California San Diego, La Jolla, CA 92037
- Howard Hughes Medical Institute, University of California San Diego, La Jolla, CA 92037
- Rady Children's Institute of Genomic Medicine, University of California San Diego, La Jolla, CA 92037
| | - Andrey Krokhotin
- Department of Pathology, Stanford Medical School, Palo Alto, CA 94305
- Department of Genetics, Stanford Medical School, Palo Alto, CA 94305
- Department of Developmental Biology, Stanford Medical School, Palo Alto, CA 94305
- Howard Hughes Medical Institute, Stanford University, Palo Alto, CA 94305
| | - Jessica J Walsh
- Nancy Pritztker Laboratory, Department of Psychiatry and Behavioral Sciences, Stanford Medical School, Palo Alto, CA 94305
| | - Hongjie Li
- Howard Hughes Medical Institute, Stanford University, Palo Alto, CA 94305
- Department of Biology, Stanford University, Palo Alto, CA 94305
| | - Hirotaka Shoji
- Division of Systems Medical Science, Institute for Comprehensive Medical Science, Fujita Health University, 470-1192 Toyoake, Aichi, Japan
| | - Shereen Ghosh
- Department of Neuroscience, University of California San Diego, La Jolla, CA 92037
- Howard Hughes Medical Institute, University of California San Diego, La Jolla, CA 92037
- Rady Children's Institute of Genomic Medicine, University of California San Diego, La Jolla, CA 92037
| | - Renee D George
- Department of Neuroscience, University of California San Diego, La Jolla, CA 92037
- Howard Hughes Medical Institute, University of California San Diego, La Jolla, CA 92037
- Rady Children's Institute of Genomic Medicine, University of California San Diego, La Jolla, CA 92037
| | - Erik L Miller
- Department of Pathology, Stanford Medical School, Palo Alto, CA 94305
- Department of Genetics, Stanford Medical School, Palo Alto, CA 94305
- Department of Developmental Biology, Stanford Medical School, Palo Alto, CA 94305
- Howard Hughes Medical Institute, Stanford University, Palo Alto, CA 94305
| | - Laura Elias
- Department of Pathology, Stanford Medical School, Palo Alto, CA 94305
- Department of Genetics, Stanford Medical School, Palo Alto, CA 94305
- Department of Developmental Biology, Stanford Medical School, Palo Alto, CA 94305
- Howard Hughes Medical Institute, Stanford University, Palo Alto, CA 94305
| | | | - Esther Y Son
- Department of Pathology, Stanford Medical School, Palo Alto, CA 94305
- Department of Genetics, Stanford Medical School, Palo Alto, CA 94305
- Department of Developmental Biology, Stanford Medical School, Palo Alto, CA 94305
- Howard Hughes Medical Institute, Stanford University, Palo Alto, CA 94305
| | - Brett T Staahl
- Department of Pathology, Stanford Medical School, Palo Alto, CA 94305
- Department of Genetics, Stanford Medical School, Palo Alto, CA 94305
- Department of Developmental Biology, Stanford Medical School, Palo Alto, CA 94305
- Howard Hughes Medical Institute, Stanford University, Palo Alto, CA 94305
| | - Seung Tae Baek
- Department of Neuroscience, University of California San Diego, La Jolla, CA 92037
- Howard Hughes Medical Institute, University of California San Diego, La Jolla, CA 92037
- Rady Children's Institute of Genomic Medicine, University of California San Diego, La Jolla, CA 92037
| | - Valentina Stanley
- Department of Neuroscience, University of California San Diego, La Jolla, CA 92037
- Howard Hughes Medical Institute, University of California San Diego, La Jolla, CA 92037
- Rady Children's Institute of Genomic Medicine, University of California San Diego, La Jolla, CA 92037
| | - Cynthia Moncada
- Department of Pathology, Stanford Medical School, Palo Alto, CA 94305
- Department of Genetics, Stanford Medical School, Palo Alto, CA 94305
- Department of Developmental Biology, Stanford Medical School, Palo Alto, CA 94305
- Howard Hughes Medical Institute, Stanford University, Palo Alto, CA 94305
| | - Zohar Shipony
- Department of Pathology, Stanford Medical School, Palo Alto, CA 94305
- Department of Genetics, Stanford Medical School, Palo Alto, CA 94305
- Department of Developmental Biology, Stanford Medical School, Palo Alto, CA 94305
- Howard Hughes Medical Institute, Stanford University, Palo Alto, CA 94305
| | - Sara B Linker
- Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, CA 92037
| | - Maria C N Marchetto
- Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, CA 92037
| | - Fred H Gage
- Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, CA 92037
| | - Dillon Chen
- Department of Neuroscience, University of California San Diego, La Jolla, CA 92037
- Howard Hughes Medical Institute, University of California San Diego, La Jolla, CA 92037
- Rady Children's Institute of Genomic Medicine, University of California San Diego, La Jolla, CA 92037
| | - Tipu Sultan
- Department of Pediatric Neurology, Institute of Child Health, Children Hospital Lahore, 54000 Lahore, Pakistan
| | - Maha S Zaki
- Clinical Genetics Department, Human Genetics and Genome Research Division, National Research Centre, 12311 Cairo, Egypt
| | | | - Tsuyoshi Miyakawa
- Division of Systems Medical Science, Institute for Comprehensive Medical Science, Fujita Health University, 470-1192 Toyoake, Aichi, Japan
| | - Liqun Luo
- Howard Hughes Medical Institute, Stanford University, Palo Alto, CA 94305
- Department of Biology, Stanford University, Palo Alto, CA 94305
| | - Robert C Malenka
- Nancy Pritztker Laboratory, Department of Psychiatry and Behavioral Sciences, Stanford Medical School, Palo Alto, CA 94305
| | - Gerald R Crabtree
- Department of Pathology, Stanford Medical School, Palo Alto, CA 94305;
- Department of Genetics, Stanford Medical School, Palo Alto, CA 94305
- Department of Developmental Biology, Stanford Medical School, Palo Alto, CA 94305
- Howard Hughes Medical Institute, Stanford University, Palo Alto, CA 94305
| | - Joseph G Gleeson
- Department of Neuroscience, University of California San Diego, La Jolla, CA 92037;
- Howard Hughes Medical Institute, University of California San Diego, La Jolla, CA 92037
- Rady Children's Institute of Genomic Medicine, University of California San Diego, La Jolla, CA 92037
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Junod SL, Kelich JM, Ma J, Yang W. Nucleocytoplasmic transport of intrinsically disordered proteins studied by high-speed super-resolution microscopy. Protein Sci 2020; 29:1459-1472. [PMID: 32096308 DOI: 10.1002/pro.3845] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2019] [Revised: 02/18/2020] [Accepted: 02/18/2020] [Indexed: 11/10/2022]
Abstract
Both natively folded and intrinsically disordered proteins (IDPs) destined for the nucleus need to transport through the nuclear pore complexes (NPCs) in eukaryotic cells. NPCs allow for passive diffusion of small folded proteins while barricading large ones, unless they are facilitated by nuclear transport receptors. However, whether nucleocytoplasmic transport of IDPs would follow these rules remains unknown. By using a high-speed super-resolution fluorescence microscopy, we have measured transport kinetics and 3D spatial locations of transport routes through native NPCs for various IDPs. Our data revealed that the rules executed for folded proteins are not well followed by the IDPs. Instead, both large and small IDPs can passively diffuse through the NPCs. Furthermore, their diffusion efficiencies and routes are differentiated by their content ratio of charged (Ch) and hydrophobic (Hy) amino acids. A Ch/Hy-ratio mechanism was finally suggested for nucleocytoplasmic transport of IDPs.
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Affiliation(s)
- Samuel L Junod
- Department of Biology, Temple University, Philadelphia, Pennsylvania
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34
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Panagiotakos G, Haveles C, Arjun A, Petrova R, Rana A, Portmann T, Paşca SP, Palmer TD, Dolmetsch RE. Aberrant calcium channel splicing drives defects in cortical differentiation in Timothy syndrome. eLife 2019; 8:51037. [PMID: 31868578 PMCID: PMC6964969 DOI: 10.7554/elife.51037] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2019] [Accepted: 12/21/2019] [Indexed: 01/02/2023] Open
Abstract
The syndromic autism spectrum disorder (ASD) Timothy syndrome (TS) is caused by a point mutation in the alternatively spliced exon 8A of the calcium channel Cav1.2. Using mouse brain and human induced pluripotent stem cells (iPSCs), we provide evidence that the TS mutation prevents a normal developmental switch in Cav1.2 exon utilization, resulting in persistent expression of gain-of-function mutant channels during neuronal differentiation. In iPSC models, the TS mutation reduces the abundance of SATB2-expressing cortical projection neurons, leading to excess CTIP2+ neurons. We show that expression of TS-Cav1.2 channels in the embryonic mouse cortex recapitulates these differentiation defects in a calcium-dependent manner and that in utero Cav1.2 gain-and-loss of function reciprocally regulates the abundance of these neuronal populations. Our findings support the idea that disruption of developmentally regulated calcium channel splicing patterns instructively alters differentiation in the developing cortex, providing important in vivo insights into the pathophysiology of a syndromic ASD.
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Affiliation(s)
- Georgia Panagiotakos
- Department of Neurobiology, Stanford University School of Medicine, Stanford, United States.,Eli & Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, United States.,Kavli Institute for Fundamental Neuroscience, University of California, San Francisco, San Francisco, United States
| | - Christos Haveles
- Eli & Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, United States.,Kavli Institute for Fundamental Neuroscience, University of California, San Francisco, San Francisco, United States
| | - Arpana Arjun
- Eli & Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, United States.,Kavli Institute for Fundamental Neuroscience, University of California, San Francisco, San Francisco, United States.,Graduate Program in Developmental and Stem Cell Biology, University of California, San Francisco, San Francisco, United States
| | - Ralitsa Petrova
- Eli & Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, United States.,Kavli Institute for Fundamental Neuroscience, University of California, San Francisco, San Francisco, United States
| | - Anshul Rana
- Graduate Program in Biochemistry, Stanford University School of Medicine, Stanford, United States
| | - Thomas Portmann
- Department of Neurobiology, Stanford University School of Medicine, Stanford, United States
| | - Sergiu P Paşca
- Department of Neurobiology, Stanford University School of Medicine, Stanford, United States.,Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, United States
| | - Theo D Palmer
- Department of Neurosurgery, Stanford University School of Medicine, Stanford, United States
| | - Ricardo E Dolmetsch
- Department of Neurobiology, Stanford University School of Medicine, Stanford, United States
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35
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Terminal neuron localization to the upper cortical plate is controlled by the transcription factor NEUROD2. Sci Rep 2019; 9:19697. [PMID: 31873146 PMCID: PMC6927953 DOI: 10.1038/s41598-019-56171-x] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2019] [Accepted: 12/06/2019] [Indexed: 12/15/2022] Open
Abstract
Excitatory neurons of the mammalian cerebral cortex are organized into six functional layers characterized by unique patterns of connectivity, as well as distinctive physiological and morphological properties. Cortical layers appear after a highly regulated migration process in which cells move from the deeper, proliferative zone toward the superficial layers. Importantly, defects in this radial migration process have been implicated in neurodevelopmental and psychiatric diseases. Here we report that during the final stages of migration, transcription factor Neurogenic Differentiation 2 (Neurod2) contributes to terminal cellular localization within the cortical plate. In mice, in utero knockdown of Neurod2 resulted in reduced numbers of neurons localized to the uppermost region of the developing cortex, also termed the primitive cortical zone. Our ChIP-Seq and RNA-Seq analyses of genes regulated by NEUROD2 in the developing cortex identified a number of key target genes with known roles in Reelin signaling, a critical regulator of neuronal migration. Our focused analysis of regulation of the Reln gene, encoding the extracellular ligand REELIN, uncovered NEUROD2 binding to conserved E-box elements in multiple introns. Furthermore, we demonstrate that knockdown of NEUROD2 in primary cortical neurons resulted in a strong increase in Reln gene expression at the mRNA level, as well as a slight upregulation at the protein level. These data reveal a new role for NEUROD2 during the late stages of neuronal migration, and our analysis of its genomic targets offers new genes with potential roles in cortical lamination.
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36
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Yap EL, Greenberg ME. Activity-Regulated Transcription: Bridging the Gap between Neural Activity and Behavior. Neuron 2019; 100:330-348. [PMID: 30359600 DOI: 10.1016/j.neuron.2018.10.013] [Citation(s) in RCA: 396] [Impact Index Per Article: 66.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2018] [Revised: 10/02/2018] [Accepted: 10/05/2018] [Indexed: 12/21/2022]
Abstract
Gene transcription is the process by which the genetic codes of organisms are read and interpreted as a set of instructions for cells to divide, differentiate, migrate, and mature. As cells function in their respective niches, transcription further allows mature cells to interact dynamically with their external environment while reliably retaining fundamental information about past experiences. In this Review, we provide an overview of the field of activity-dependent transcription in the vertebrate brain and highlight contemporary work that ranges from studies of activity-dependent chromatin modifications to plasticity mechanisms underlying adaptive behaviors. We identify key gaps in knowledge and propose integrated approaches toward a deeper understanding of how activity-dependent transcription promotes the refinement and plasticity of neural circuits for cognitive function.
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Affiliation(s)
- Ee-Lynn Yap
- Department of Neurobiology, Harvard Medical School, 220 Longwood Avenue, Boston, MA 02115, USA; Program in Neuroscience, Harvard Medical School, 220 Longwood Avenue, Boston, MA 02115, USA
| | - Michael E Greenberg
- Department of Neurobiology, Harvard Medical School, 220 Longwood Avenue, Boston, MA 02115, USA.
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37
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Volpe JJ. Dysmaturation of Premature Brain: Importance, Cellular Mechanisms, and Potential Interventions. Pediatr Neurol 2019; 95:42-66. [PMID: 30975474 DOI: 10.1016/j.pediatrneurol.2019.02.016] [Citation(s) in RCA: 208] [Impact Index Per Article: 34.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2019] [Revised: 02/12/2019] [Accepted: 02/19/2019] [Indexed: 02/07/2023]
Abstract
Prematurity, especially preterm birth (less than 32 weeks' gestation), is common and associated with high rates of both survival and neurodevelopmental disability, especially apparent in cognitive spheres. The neuropathological substrate of this disability is now recognized to be related to a variety of dysmaturational disturbances of the brain. These disturbances follow initial brain injury, particularly cerebral white matter injury, and involve many of the extraordinary array of developmental events active in cerebral white and gray matter structures during the premature period. This review delineates these developmental events and the dysmaturational disturbances that occur in premature infants. The cellular mechanisms involved in the genesis of the dysmaturation are emphasized, with particular focus on the preoligodendrocyte. A central role for the diffusely distributed activated microglia and reactive astrocytes in the dysmaturation is now apparent. As these dysmaturational cellular mechanisms appear to occur over a relatively long time window, interventions to prevent or ameliorate the dysmaturation, that is, neurorestorative interventions, seem possible. Such interventions include pharmacologic agents, especially erythropoietin, and particular attention has also been paid to such nutritional factors as quality and source of milk, breastfeeding, polyunsaturated fatty acids, iron, and zinc. Recent studies also suggest a potent role for interventions directed at various experiential factors in the neonatal period and infancy, i.e., provision of optimal auditory and visual exposures, minimization of pain and stress, and a variety of other means of environmental behavioral enrichment, in enhancing brain development.
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Affiliation(s)
- Joseph J Volpe
- Department of Neurology, Harvard Medical School, Boston, Massachusetts; Department of Pediatric Newborn Medicine, Harvard Medical School, Boston, Massachusetts.
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38
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Kuehner JN, Bruggeman EC, Wen Z, Yao B. Epigenetic Regulations in Neuropsychiatric Disorders. Front Genet 2019; 10:268. [PMID: 31019524 PMCID: PMC6458251 DOI: 10.3389/fgene.2019.00268] [Citation(s) in RCA: 83] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2018] [Accepted: 03/11/2019] [Indexed: 12/14/2022] Open
Abstract
Precise genetic and epigenetic spatiotemporal regulation of gene expression is critical for proper brain development, function and circuitry formation in the mammalian central nervous system. Neuronal differentiation processes are tightly regulated by epigenetic mechanisms including DNA methylation, histone modifications, chromatin remodelers and non-coding RNAs. Dysregulation of any of these pathways is detrimental to normal neuronal development and functions, which can result in devastating neuropsychiatric disorders, such as depression, schizophrenia and autism spectrum disorders. In this review, we focus on the current understanding of epigenetic regulations in brain development and functions, as well as their implications in neuropsychiatric disorders.
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Affiliation(s)
- Janise N Kuehner
- Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, United States
| | - Emily C Bruggeman
- Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, United States
| | - Zhexing Wen
- Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, United States.,Department of Cell Biology, Emory University School of Medicine, Atlanta, GA, United States.,Department of Neurology, Emory University School of Medicine, Atlanta, GA, United States
| | - Bing Yao
- Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, United States
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Cheng C, Yang K, Wu X, Zhang Y, Shan S, Gitler A, Ghosh A, Qiu Z. Loss of CREST leads to neuroinflammatory responses and ALS-like motor defects in mice. Transl Neurodegener 2019; 8:13. [PMID: 30976389 PMCID: PMC6444434 DOI: 10.1186/s40035-019-0152-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2018] [Accepted: 03/18/2019] [Indexed: 12/25/2022] Open
Abstract
Background Amyotrophic lateral sclerosis (ALS) is a late onset neurodegenerative disease with fast progression. ALS has heavy genetic components in which a series of genetic mutations have been identified. In 2013, Mutations of the CREST gene (also known as SS18L1), which functions as a calcium-regulated transcriptional activator, were found in sporadic ALS patients. However, the pathogenic causality and mechanisms of ALS-associated mutations of CREST remain to be determined. Methods In this study, we constructed CREST knockout and Q394X knock-in mice with CRISPR/Cas9 system. Using biochemical and imaging tools, we illustrated core pathological phenotypes in CREST mutant mice and claimed the possible pathogenic mechanisms. Furthermore, we also observed locomotion defects in CREST mutant mice with behavioural tests. Results We demonstrate that ALS-related CREST-Q388X mutation exhibits loss-of-function effects. Importantly, the microglial activation was prevalent in CREST haploinsufficiency mice and Q394X mice mimicking the human CREST Q388X mutation. Furthermore, we showed that both CREST haploinsufficiency and Q394X mice displayed deficits in motor coordination. Finally, we identified the critical role of CREST-BRG1 complex in repressing the expression of immune-related cytokines including Ccl2 and Cxcl10 in neurons, via histone deacetylation, providing the molecular mechanisms underlying inflammatory responses within mice lack of CREST. Conclusion Our findings indicate that elevated inflammatory responses in a subset of ALS may be caused by neuron-derived factors, suggesting potential therapeutic methods through inflammation pathways.
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Affiliation(s)
- Cheng Cheng
- 1Institute of Neuroscience, State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031 China
| | - Kan Yang
- 1Institute of Neuroscience, State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031 China
| | - Xinwei Wu
- 2Xiangya Hospital, Central South University, Changsha, 410008 China
| | - Yuefang Zhang
- 1Institute of Neuroscience, State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031 China
| | - Shifang Shan
- 1Institute of Neuroscience, State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031 China
| | - Aaron Gitler
- 3Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305 USA
| | - Anirvan Ghosh
- 4Research and Early Development, Biogen, Cambridge, MA 02142 USA
| | - Zilong Qiu
- 1Institute of Neuroscience, State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031 China
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40
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Alfert A, Moreno N, Kerl K. The BAF complex in development and disease. Epigenetics Chromatin 2019; 12:19. [PMID: 30898143 PMCID: PMC6427853 DOI: 10.1186/s13072-019-0264-y] [Citation(s) in RCA: 167] [Impact Index Per Article: 27.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2018] [Accepted: 03/13/2019] [Indexed: 01/16/2023] Open
Abstract
The ATP-dependent chromatin remodelling complex BAF (= mammalian SWI/SNF complex) is crucial for the regulation of gene expression and differentiation. In the course of evolution from yeast to mammals, the BAF complex evolved an immense complexity with a high number of subunits encoded by gene families. In this way, tissue-specific BAF function and regulation of development begin with the combinatorial assembly of distinct BAF complexes such as esBAF, npBAF and nBAF. Furthermore, whole-genome sequencing reveals the tremendous role BAF complex mutations have in both neurodevelopmental disorders and human malignancies. Therefore, gaining a more elaborate insight into how BAF complex assembly influences its function and which role distinct subunits play, will hopefully give rise to a better understanding of disease pathogenesis and ultimately to new treatments for many human diseases.
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Affiliation(s)
- Amelie Alfert
- Department of Paediatric Haematology and Oncology, University Children’s Hospital Muenster, Domagkstraße 24, 48149 Muenster, Germany
| | - Natalia Moreno
- Department of Paediatric Haematology and Oncology, University Children’s Hospital Muenster, Domagkstraße 24, 48149 Muenster, Germany
| | - Kornelius Kerl
- Department of Paediatric Haematology and Oncology, University Children’s Hospital Muenster, Domagkstraße 24, 48149 Muenster, Germany
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41
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Alaghband Y, Kramár E, Kwapis JL, Kim ES, Hemstedt TJ, López AJ, White AO, Al-Kachak A, Aimiuwu OV, Bodinayake KK, Oparaugo NC, Han J, Lattal KM, Wood MA. CREST in the Nucleus Accumbens Core Regulates Cocaine Conditioned Place Preference, Cocaine-Seeking Behavior, and Synaptic Plasticity. J Neurosci 2018; 38:9514-9526. [PMID: 30228227 PMCID: PMC6209848 DOI: 10.1523/jneurosci.2911-17.2018] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2017] [Revised: 08/29/2018] [Accepted: 09/06/2018] [Indexed: 11/21/2022] Open
Abstract
Epigenetic mechanisms result in persistent changes at the cellular level that can lead to long-lasting behavioral adaptations. Nucleosome remodeling is a major epigenetic mechanism that has not been well explored with regards to drug-seeking behaviors. Nucleosome remodeling is performed by multi-subunit complexes that interact with DNA or chromatin structure and possess an ATP-dependent enzyme to disrupt nucleosome-DNA contacts and ultimately regulate gene expression. Calcium responsive transactivator (CREST) is a transcriptional activator that interacts with enzymes involved in both histone acetylation and nucleosome remodeling. Here, we examined the effects of knocking down CREST in the nucleus accumbens (NAc) core on drug-seeking behavior and synaptic plasticity in male mice as well as drug-seeking in male rats. Knocking down CREST in the NAc core results in impaired cocaine-induced conditioned place preference (CPP) as well as theta-induced long-term potentiation in the NAc core. Further, similar to the CPP findings, using a self-administration procedure, we found that CREST knockdown in the NAc core of male rats had no effect on instrumental responding for cocaine itself on a first-order schedule, but did significantly attenuate responding on a second-order chain schedule, in which responding has a weaker association with cocaine. Together, these results suggest that CREST in the NAc core is required for cocaine-induced CPP, synaptic plasticity, as well as cocaine-seeking behavior.SIGNIFICANCE STATEMENT This study demonstrates a key role for the role of Calcium responsive transactivator (CREST), a transcriptional activator, in the nucleus accumbens (NAc) core with regard to cocaine-induced conditioned place preference (CPP), self-administration (SA), and synaptic plasticity. CREST is a unique transcriptional regulator that can recruit enzymes from two different major epigenetic mechanisms: histone acetylation and nucleosome remodeling. In this study we also found that the level of potentiation in the NAc core correlated with whether or not animals formed a CPP. Together the results indicate that CREST is a key downstream regulator of cocaine action in the NAc.
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Affiliation(s)
- Yasaman Alaghband
- Department of Neurobiology and Behavior, Center for the Neurobiology of Learning and Memory
- Irvine Center for Addiction Neuroscience
- Center for the Neurobiology of Learning and Memory, Irvine, California, 92697, and
| | - Enikö Kramár
- Department of Neurobiology and Behavior, Center for the Neurobiology of Learning and Memory
- Center for the Neurobiology of Learning and Memory, Irvine, California, 92697, and
| | - Janine L Kwapis
- Department of Neurobiology and Behavior, Center for the Neurobiology of Learning and Memory
- Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, Irvine, California 92697
- Center for the Neurobiology of Learning and Memory, Irvine, California, 92697, and
| | - Earnest S Kim
- Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, Oregon 97239
| | - Thekla J Hemstedt
- Department of Neurobiology and Behavior, Center for the Neurobiology of Learning and Memory
- Center for the Neurobiology of Learning and Memory, Irvine, California, 92697, and
| | - Alberto J López
- Department of Neurobiology and Behavior, Center for the Neurobiology of Learning and Memory
- Irvine Center for Addiction Neuroscience
- Center for the Neurobiology of Learning and Memory, Irvine, California, 92697, and
| | - André O White
- Department of Neurobiology and Behavior, Center for the Neurobiology of Learning and Memory
- Irvine Center for Addiction Neuroscience
- Center for the Neurobiology of Learning and Memory, Irvine, California, 92697, and
| | - Amni Al-Kachak
- Department of Neurobiology and Behavior, Center for the Neurobiology of Learning and Memory
- Center for the Neurobiology of Learning and Memory, Irvine, California, 92697, and
| | - Osasumwen V Aimiuwu
- Department of Neurobiology and Behavior, Center for the Neurobiology of Learning and Memory
- Center for the Neurobiology of Learning and Memory, Irvine, California, 92697, and
| | - Kasuni K Bodinayake
- Department of Neurobiology and Behavior, Center for the Neurobiology of Learning and Memory
- Center for the Neurobiology of Learning and Memory, Irvine, California, 92697, and
| | - Nicole C Oparaugo
- Department of Neurobiology and Behavior, Center for the Neurobiology of Learning and Memory
- Center for the Neurobiology of Learning and Memory, Irvine, California, 92697, and
| | - Joseph Han
- Department of Neurobiology and Behavior, Center for the Neurobiology of Learning and Memory
- Center for the Neurobiology of Learning and Memory, Irvine, California, 92697, and
| | - K Matthew Lattal
- Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, Oregon 97239
| | - Marcelo A Wood
- Department of Neurobiology and Behavior, Center for the Neurobiology of Learning and Memory,
- Irvine Center for Addiction Neuroscience
- Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, Irvine, California 92697
- Center for the Neurobiology of Learning and Memory, Irvine, California, 92697, and
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Lira M, Arancibia D, Orrego PR, Montenegro-Venegas C, Cruz Y, García J, Leal-Ortiz S, Godoy JA, Gundelfinger ED, Inestrosa NC, Garner CC, Zamorano P, Torres VI. The Exocyst Component Exo70 Modulates Dendrite Arbor Formation, Synapse Density, and Spine Maturation in Primary Hippocampal Neurons. Mol Neurobiol 2018; 56:4620-4638. [DOI: 10.1007/s12035-018-1378-0] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2018] [Accepted: 10/01/2018] [Indexed: 02/07/2023]
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43
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Lu YL, Yoo AS. Mechanistic Insights Into MicroRNA-Induced Neuronal Reprogramming of Human Adult Fibroblasts. Front Neurosci 2018; 12:522. [PMID: 30116172 PMCID: PMC6083049 DOI: 10.3389/fnins.2018.00522] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2018] [Accepted: 07/12/2018] [Indexed: 12/16/2022] Open
Abstract
The use of transcriptional factors as cell fate regulators are often the primary focus in the direct reprogramming of somatic cells into neurons. However, in human adult fibroblasts, deriving functionally mature neurons with high efficiency requires additional neurogenic factors such as microRNAs (miRNAs) to evoke a neuronal state permissive to transcription factors to exert their reprogramming activities. As such, increasing evidence suggests brain-enriched miRNAs, miR-9/9∗ and miR-124, as potent neurogenic molecules through simultaneously targeting of anti-neurogenic effectors while allowing additional transcription factors to generate specific subtypes of human neurons. In this review, we will focus on methods that utilize neuronal miRNAs and provide mechanistic insights by which neuronal miRNAs, in synergism with brain-region specific transcription factors, drive the conversion of human fibroblasts into clinically relevant subtypes of neurons. Furthermore, we will provide insights into the age signature of directly converted neurons and how the converted human neurons can be utilized to model late-onset neurodegenerative disorders.
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Affiliation(s)
- Ya-Lin Lu
- Department of Developmental Biology, School of Medicine, Washington University in St. Louis, St. Louis, MO, United States.,Program in Developmental, Regenerative and Stem Cell Biology, School of Medicine, Washington University in St. Louis, St. Louis, MO, United States
| | - Andrew S Yoo
- Department of Developmental Biology, School of Medicine, Washington University in St. Louis, St. Louis, MO, United States
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44
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Sokpor G, Castro-Hernandez R, Rosenbusch J, Staiger JF, Tuoc T. ATP-Dependent Chromatin Remodeling During Cortical Neurogenesis. Front Neurosci 2018; 12:226. [PMID: 29686607 PMCID: PMC5900035 DOI: 10.3389/fnins.2018.00226] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2017] [Accepted: 03/22/2018] [Indexed: 12/20/2022] Open
Abstract
The generation of individual neurons (neurogenesis) during cortical development occurs in discrete steps that are subtly regulated and orchestrated to ensure normal histogenesis and function of the cortex. Notably, various gene expression programs are known to critically drive many facets of neurogenesis with a high level of specificity during brain development. Typically, precise regulation of gene expression patterns ensures that key events like proliferation and differentiation of neural progenitors, specification of neuronal subtypes, as well as migration and maturation of neurons in the developing cortex occur properly. ATP-dependent chromatin remodeling complexes regulate gene expression through utilization of energy from ATP hydrolysis to reorganize chromatin structure. These chromatin remodeling complexes are characteristically multimeric, with some capable of adopting functionally distinct conformations via subunit reconstitution to perform specific roles in major aspects of cortical neurogenesis. In this review, we highlight the functions of such chromatin remodelers during cortical development. We also bring together various proposed mechanisms by which ATP-dependent chromatin remodelers function individually or in concert, to specifically modulate vital steps in cortical neurogenesis.
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Affiliation(s)
- Godwin Sokpor
- Institute for Neuroanatomy, University Medical Center, Georg-August-University Goettingen, Goettingen, Germany
| | - Ricardo Castro-Hernandez
- Institute for Neuroanatomy, University Medical Center, Georg-August-University Goettingen, Goettingen, Germany
| | - Joachim Rosenbusch
- Institute for Neuroanatomy, University Medical Center, Georg-August-University Goettingen, Goettingen, Germany
| | - Jochen F Staiger
- Institute for Neuroanatomy, University Medical Center, Georg-August-University Goettingen, Goettingen, Germany.,DFG Center for Nanoscale Microscopy and Molecular Physiology of the Brain, Goettingen, Germany
| | - Tran Tuoc
- Institute for Neuroanatomy, University Medical Center, Georg-August-University Goettingen, Goettingen, Germany.,DFG Center for Nanoscale Microscopy and Molecular Physiology of the Brain, Goettingen, Germany
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45
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Tibshirani M, Zhao B, Gentil BJ, Minotti S, Marques C, Keith J, Rogaeva E, Zinman L, Rouaux C, Robertson J, Durham HD. Dysregulation of chromatin remodelling complexes in amyotrophic lateral sclerosis. Hum Mol Genet 2018; 26:4142-4152. [PMID: 28973294 DOI: 10.1093/hmg/ddx301] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2017] [Accepted: 07/21/2017] [Indexed: 12/12/2022] Open
Abstract
Amyotrophic lateral sclerosis is a fatal neurodegenerative disease with paralysis resulting from dysfunction and loss of motor neurons. A common neuropathological finding is attrition of motor neuron dendrites, which make central connections vital to motor control. The chromatin remodelling complex, neuronal Brahma-related gene 1 (Brg1)-associated factor complex (nBAF), is critical for neuronal differentiation, dendritic extension and synaptic function. We have identified loss of the crucial nBAF subunits Brg1, Brg1-associated factor 53b and calcium responsive transactivator in cultured motor neurons expressing FUS or TAR-DNA Binding Protein 43 (TDP-43) mutants linked to familial ALS. When plasmids encoding wild-type or mutant human FUS or TDP-43 were expressed in motor neurons of dissociated spinal cord cultures prepared from E13 mice, mutant proteins in particular accumulated in the cytoplasm. Immunolabelling of nBAF subunits was reduced in proportion to loss of nuclear FUS or TDP-43 and depletion of Brg1 was associated with nuclear retention of Brg1 mRNA. Dendritic attrition (loss of intermediate and terminal dendritic branches) occurred in motor neurons expressing mutant, but not wild-type, FUS or TDP-43. This attrition was delayed by ectopic over-expression of Brg1 and was reproduced by inhibiting Brg1 activity either through genetic manipulation or treatment with the chemical inhibitor, (E)-1-(2-Hydroxyphenyl)-3-((1R, 4R)-5-(pyridin-2-yl)-2, 5-diazabicyclo[2.2.1]heptan-2-yl)prop-2-en-1-one, demonstrating the importance of Brg1 to maintenance of dendritic architecture. Loss of nBAF subunits was also documented in spinal motor neurons in autopsy tissue from familial amyotrophic sclerosis (chromosome 9 open reading frame 72 with G4C2 nucleotide expansion) and from sporadic cases with no identified mutation, pointing to dysfunction of nBAF chromatin remodelling in multiple forms of ALS.
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Affiliation(s)
- Michael Tibshirani
- Department of Neurology and Neurosurgery and the Montreal Neurological Institute, McGill University, Montreal, QC H3A 2B3, Canada
| | - Beibei Zhao
- Tanz Centre for Research in Neurodegenerative Disease, University of Toronto, Toronto, ON M5T 2S8, Canada
| | - Benoit J Gentil
- Department of Neurology and Neurosurgery and the Montreal Neurological Institute, McGill University, Montreal, QC H3A 2B3, Canada
| | - Sandra Minotti
- Department of Neurology and Neurosurgery and the Montreal Neurological Institute, McGill University, Montreal, QC H3A 2B3, Canada
| | - Christine Marques
- Inserm U1118, Faculté de Médecine, Université de Strasbourg, 67 085 Strasbourg Cedex, France
| | - Julia Keith
- Department of Laboratory Medicine and Pathobiology, Sunnybrook Health Sciences Center, University of Toronto, Toronto, ON M4N 3M5, Canada
| | - Ekaterina Rogaeva
- Tanz Centre for Research in Neurodegenerative Disease, University of Toronto, Toronto, ON M5T 2S8, Canada
| | - Lorne Zinman
- Department of Laboratory Medicine and Pathobiology, Sunnybrook Health Sciences Center, University of Toronto, Toronto, ON M4N 3M5, Canada
| | - Caroline Rouaux
- Inserm U1118, Faculté de Médecine, Université de Strasbourg, 67 085 Strasbourg Cedex, France
| | - Janice Robertson
- Tanz Centre for Research in Neurodegenerative Disease, University of Toronto, Toronto, ON M5T 2S8, Canada.,Department of Laboratory Medicine and Pathobiology, Sunnybrook Health Sciences Center, University of Toronto, Toronto, ON M4N 3M5, Canada
| | - Heather D Durham
- Department of Neurology and Neurosurgery and the Montreal Neurological Institute, McGill University, Montreal, QC H3A 2B3, Canada
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Shu G, Kramár EA, López AJ, Huynh G, Wood MA, Kwapis JL. Deleting HDAC3 rescues long-term memory impairments induced by disruption of the neuron-specific chromatin remodeling subunit BAF53b. ACTA ACUST UNITED AC 2018; 25:109-114. [PMID: 29449454 PMCID: PMC5817283 DOI: 10.1101/lm.046920.117] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2017] [Accepted: 12/19/2017] [Indexed: 12/31/2022]
Abstract
Multiple epigenetic mechanisms, including histone acetylation and nucleosome remodeling, are known to be involved in long-term memory formation. Enhancing histone acetylation by deleting histone deacetylases, like HDAC3, typically enhances long-term memory formation. In contrast, disrupting nucleosome remodeling by blocking the neuron-specific chromatin remodeling subunit BAF53b impairs long-term memory. Here, we show that deleting HDAC3 can ameliorate the impairments in both long-term memory and synaptic plasticity caused by BAF53b mutation. This suggests a dynamic interplay exists between histone acetylation/deacetylation and nucleosome remodeling mechanisms in the regulation of memory formation.
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Affiliation(s)
- Guanhua Shu
- Department of Neurobiology and Behavior, University of California, Irvine, California, 92697, USA.,Center for Neurobiology of Learning and Memory, Irvine, California, 92697, USA
| | - Enikö A Kramár
- Department of Neurobiology and Behavior, University of California, Irvine, California, 92697, USA.,Center for Neurobiology of Learning and Memory, Irvine, California, 92697, USA
| | - Alberto J López
- Department of Neurobiology and Behavior, University of California, Irvine, California, 92697, USA.,Center for Neurobiology of Learning and Memory, Irvine, California, 92697, USA
| | - Grace Huynh
- Department of Neurobiology and Behavior, University of California, Irvine, California, 92697, USA.,Center for Neurobiology of Learning and Memory, Irvine, California, 92697, USA
| | - Marcelo A Wood
- Department of Neurobiology and Behavior, University of California, Irvine, California, 92697, USA.,Center for Neurobiology of Learning and Memory, Irvine, California, 92697, USA
| | - Janine L Kwapis
- Department of Neurobiology and Behavior, University of California, Irvine, California, 92697, USA.,Center for Neurobiology of Learning and Memory, Irvine, California, 92697, USA
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Uversky VN. The roles of intrinsic disorder-based liquid-liquid phase transitions in the "Dr. Jekyll-Mr. Hyde" behavior of proteins involved in amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Autophagy 2017; 13:2115-2162. [PMID: 28980860 DOI: 10.1080/15548627.2017.1384889] [Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Pathological developments leading to amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are associated with misbehavior of several key proteins, such as SOD1 (superoxide dismutase 1), TARDBP/TDP-43, FUS, C9orf72, and dipeptide repeat proteins generated as a result of the translation of the intronic hexanucleotide expansions in the C9orf72 gene, PFN1 (profilin 1), GLE1 (GLE1, RNA export mediator), PURA (purine rich element binding protein A), FLCN (folliculin), RBM45 (RNA binding motif protein 45), SS18L1/CREST, HNRNPA1 (heterogeneous nuclear ribonucleoprotein A1), HNRNPA2B1 (heterogeneous nuclear ribonucleoprotein A2/B1), ATXN2 (ataxin 2), MAPT (microtubule associated protein tau), and TIA1 (TIA1 cytotoxic granule associated RNA binding protein). Although these proteins are structurally and functionally different and have rather different pathological functions, they all possess some levels of intrinsic disorder and are either directly engaged in or are at least related to the physiological liquid-liquid phase transitions (LLPTs) leading to the formation of various proteinaceous membrane-less organelles (PMLOs), both normal and pathological. This review describes the normal and pathological functions of these ALS- and FTLD-related proteins, describes their major structural properties, glances at their intrinsic disorder status, and analyzes the involvement of these proteins in the formation of normal and pathological PMLOs, with the ultimate goal of better understanding the roles of LLPTs and intrinsic disorder in the "Dr. Jekyll-Mr. Hyde" behavior of those proteins.
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Affiliation(s)
- Vladimir N Uversky
- a Department of Molecular Medicine and USF Health Byrd Alzheimer's Research Institute , Morsani College of Medicine , University of South Florida , Tampa , FL , USA.,b Institute for Biological Instrumentation of the Russian Academy of Sciences , Pushchino, Moscow region , Russia
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48
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Madabhushi R, Kim TK. Emerging themes in neuronal activity-dependent gene expression. Mol Cell Neurosci 2017; 87:27-34. [PMID: 29254824 DOI: 10.1016/j.mcn.2017.11.009] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2017] [Revised: 10/23/2017] [Accepted: 11/08/2017] [Indexed: 12/29/2022] Open
Abstract
In this review, we attempt to discuss emerging themes in the regulation of neuronal activity-regulated genes, focusing primarily on an important subset of immediate-early genes. We first discuss earlier studies that have illuminated the role of cis-acting elements within the promoters of immediate-early genes, the corresponding transcription factors that bind these elements, and the roles of major activity-regulated signaling pathways. However, our emphasis is on new studies that have revealed an important role for epigenetic and topological mechanisms, including enhancer-promoter interactions, enhancer RNAs (eRNAs), and activity-induced DNA breaks, that have emerged as important factors that govern the temporal dynamics of activity-induced gene transcription.
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Affiliation(s)
- Ram Madabhushi
- Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX, USA; Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX, USA.
| | - Tae-Kyung Kim
- Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX, USA.
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49
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Ledda F, Paratcha G. Mechanisms regulating dendritic arbor patterning. Cell Mol Life Sci 2017; 74:4511-4537. [PMID: 28735442 PMCID: PMC11107629 DOI: 10.1007/s00018-017-2588-8] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2016] [Revised: 06/14/2017] [Accepted: 07/06/2017] [Indexed: 12/17/2022]
Abstract
The nervous system is populated by diverse types of neurons, each of which has dendritic trees with strikingly different morphologies. These neuron-specific morphologies determine how dendritic trees integrate thousands of synaptic inputs to generate different firing properties. To ensure proper neuronal function and connectivity, it is necessary that dendrite patterns are precisely controlled and coordinated with synaptic activity. Here, we summarize the molecular and cellular mechanisms that regulate the formation of cell type-specific dendrite patterns during development. We focus on different aspects of vertebrate dendrite patterning that are particularly important in determining the neuronal function; such as the shape, branching, orientation and size of the arbors as well as the development of dendritic spine protrusions that receive excitatory inputs and compartmentalize postsynaptic responses. Additionally, we briefly comment on the implications of aberrant dendritic morphology for nervous system disease.
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Affiliation(s)
- Fernanda Ledda
- Division of Molecular and Cellular Neuroscience, Institute of Cell Biology and Neuroscience (IBCN)-CONICET, School of Medicine, University of Buenos Aires (UBA), Paraguay 2155, 3rd Floor, CABA, 1121, Buenos Aires, Argentina
| | - Gustavo Paratcha
- Division of Molecular and Cellular Neuroscience, Institute of Cell Biology and Neuroscience (IBCN)-CONICET, School of Medicine, University of Buenos Aires (UBA), Paraguay 2155, 3rd Floor, CABA, 1121, Buenos Aires, Argentina.
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50
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Mathies LD, Aliev F, Davies AG, Dick DM, Bettinger JC. Variation in SWI/SNF Chromatin Remodeling Complex Proteins is Associated with Alcohol Dependence and Antisocial Behavior in Human Populations. Alcohol Clin Exp Res 2017; 41:2033-2040. [PMID: 28981154 DOI: 10.1111/acer.13514] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2017] [Accepted: 09/28/2017] [Indexed: 01/21/2023]
Abstract
BACKGROUND Testing for direct gene or single nucleotide polymorphism replication of association across studies may not capture the true importance of a candidate locus; rather, we suggest that relevant replication across studies may be found at the level of a biological process. We previously observed that variation in 2 members of the switching defective/sucrose nonfermenting (SWI/SNF) chromatin remodeling complex is associated with alcohol dependence (AD) in the Irish Affected Sib Pair Study for Alcohol Dependence. Here, we tested for association with alcohol-related outcomes using a set of genes functioning in the SWI/SNF complex in 2 independent samples. METHODS We used a set-based analysis to examine the 29 genes of the SWI/SNF complex for evidence of association with (i) AD in the adult Collaborative Study on the Genetics of Alcoholism (COGA) case-control sample and (ii) antisocial behavior, hypothesized to be a genetically related developmental precursor, in a younger population sample (Spit for Science [S4S]). RESULTS We found evidence for association of the SWI/SNF complex with AD in COGA (p = 0.0435) and more general antisocial behavior in S4S (p = 0.00026). The genes that contributed most strongly to the signal in COGA were SS18L1, SMARCD1, BRD7, BCL7B, SMARCB1, and BCL11A. In the S4S sample, ACTB, ARID2, BCL11A, BCL11B, BCL7B, BCL7C, DPF2, and DPF3 all contributed strongly to the signal. CONCLUSIONS We detected associations between the SWI/SNF complex and AD in an adult population selected from treatment-seeking probands and antisocial behavior in an adolescent population sample. This provides strong support for a role for SWI/SNF in the development of alcohol-related problems.
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Affiliation(s)
- Laura D Mathies
- Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia
| | - Fazil Aliev
- Department of Psychology, Virginia Commonwealth University, Richmond, Virginia.,Karabuk University, Karabuk, Turkey
| | | | - Andrew G Davies
- Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia.,Virginia Commonwealth University Alcohol Research Center, Richmond, Virginia
| | - Danielle M Dick
- Department of Psychology, Virginia Commonwealth University, Richmond, Virginia.,Virginia Commonwealth University Alcohol Research Center, Richmond, Virginia.,Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, Virginia
| | - Jill C Bettinger
- Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia.,Virginia Commonwealth University Alcohol Research Center, Richmond, Virginia
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