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Germline Chd8 haploinsufficiency alters brain development in mouse
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Abstract
The chromatin remodeling gene CHD8 represents a central node in neurodevelopmental gene networks implicated in autism. We examined the impact of germline heterozygous frameshift Chd8 mutation on neurodevelopment in mice. Chd8+/del5 mice displayed normal social interactions with no repetitive behaviors but exhibited cognitive impairment correlated with increased regional brain volume, validating that phenotypes of Chd8+/del5 mice overlap pathology reported in humans with CHD8 mutations. We applied network analysis to characterize neurodevelopmental gene expression, revealing widespread transcriptional changes in Chd8+/del5 mice across pathways disrupted in neurodevelopmental disorders, including neurogenesis, synaptic processes and neuroimmune signaling. We identified a co-expression module with peak expression in early brain development featuring dysregulation of RNA processing, chromatin remodeling and cell-cycle genes enriched for promoter binding by Chd8, and we validated increased neuronal proliferation and developmental splicing perturbation in Chd8+/del5 mice. This integrative analysis offers an initial picture of the consequences of Chd8 haploinsufficiency for brain development.
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“Studies on CHD8 and iPS-derived ASD neurons indicate the dysregulation of proliferation and macrocephaly in ASD could be linked to the disruption of these signaling pathways and shortened G1/S transition[54, 55, 57, 94, 183, 192, 193].”
From The ASD Living Biology: from cell proliferation to clinical phenotype (2019) · cites this paper as [183]
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Self-citation
Metadata
- Authors
- Gompers, A. L., Su-Feher, L., Ellegood, J., Copping, N. A., Riyadh, M. A., Stradleigh, T. W., Pride, M. C., Schaffler, M. D., Wade, A. A., Catta-Preta, R., Zdilar, I., Louis, S., Kaushik, G., Mannion, B. J., Plajzer-Frick, I., Afzal, V., Visel, A., Pennacchio, L. A., Dickel, D. E., Lerch, J. P., Crawley, J. N., Zarbalis, K. S., Silverman, J. L., & Nord, A. S.
- Affiliations
- University of California, Davis (US)
- Hospital for Sick Children (CA)
- Shriners Hospitals for Children - Northern California (US)
- Lawrence Berkeley National Laboratory (US)
- University of Toronto (CA)
- Corresponding author
- Nord, Alex S
- ORCID
- Su-Feher, Linda
- Ellegood, Jacob
- Riyadh, M Asrafuzzaman
- Stradleigh, Tyler W
- Schaffler, Melanie D
- Wade, A Ayanna
- Catta-Preta, Rinaldo
- Zdilar, Iva
- Louis, Shreya
- Mannion, Brandon J
- Afzal, Veena
- Visel, Axel
- Pennacchio, Len A
- Dickel, Diane E
- Lerch, Jason P
- Crawley, Jacqueline N
- Zarbalis, Konstantinos S
- Silverman, Jill L
- Nord, Alex S
- Venue
- Nature Neuroscience
- Published
- 2017-06-26
- Volume
- 20
- Issue
- 8
- Pages
- 1062-1073
- ISSN
- 1097-6256 (ISSN-L)
- 1546-1726
- PMC
- PMC6008102
- OpenAlex
- W2687519416
- Cited by
- 266
- References
- 98
- Citations by year
- 2026: 18 · 2025: 22 · 2024: 23 · 2023: 21 · 2022: 21 · 2021: 52 · 2020: 48 · 2019: 27 · 2018: 26 · 2017: 8
- FWCI
- 19.79
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Neuroscience (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- OSTI OAI (U.S. Department of Energy Office of Scientific and Technical Information) (submittedVersion)
- Funders
- U.S. Department of Energy (-AC02-05CH11231, 05CH11231, DE AC02 05CH11231, Contract DE-AC02-05CH11231., DE-AC02-)
- University of California Berkeley (DE-AC02-05CH11231)
- Ontario Brain Institute
- Fondation Brain Canada
- MIND Institute, University of California, Davis (U54 HD 079125, HD079125)
- Conselho Nacional de Desenvolvimento Científico e Tecnológico (DE-AC02-05CH11231)
- National Institutes of Health (DE-AC02–05CH11231, GM008799, GM119831, GM007377)
- University of California, Davis (T32-GM008799, U54 HD079125, GM007377)
- Intellectual and Developmental Disabilities Research Center (U54-HD079125)
- Ciência sem Fronteiras
- National Heart, Lung, and Blood Institute (R24HL123879, UM1HL098166)
- National Human Genome Research Institute (U54HG006997, R01HG003988)
- National Institute of General Medical Sciences (T32GM008799, T32GM007377, DE-AC02-05CH11231, GM119831, GM007377, GM008799, R35GM119831)
- National Institute of Neurological Disorders and Stroke (R01NS085709)
- National Institute of Dental and Craniofacial Research (U01DE024427)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (U54HD079125)
- Lawrence Berkeley National Laboratory (UM1HL098166, AC02‐05CH11231, DE-AC02-05CH11231, R24HL123879, U54HG006997, R01HG003988, 05CH11231, U01DE024427)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
- Keywords
- CHD8, haploinsufficiency, autism spectrum disorder, brain development, chromatin remodeling, cognitive impairment, regional brain volume, neurogenesis, synaptic processes, neuroimmune signaling, RNA processing, alternative splicing, neuronal proliferation, promoter binding
- MeSH terms
- Animals, Brain, Chromatin, DNA-Binding Proteins, Mice, Transgenic, Mutation, Phenotype, Transcription Factors, Gene Expression Regulation, Developmental, Cell Cycle Proteins, Gene Regulatory Networks, Haploinsufficiency
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
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