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Germline Chd8 haploinsufficiency alters brain development in mouse
Open accessPublished version of a preprint
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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The ASD Living Biology: from cell proliferation to clinical phenotype
Courchesne, E., Pramparo, T., Gazestani, V. H., Lombardo, M. V., Pierce, K., & Lewis, N. E. (2019) · Molecular Psychiatry · doi:10.1038/s41380-018-0056-y · Cited by 333
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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
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