Germline Chd8 haploinsufficiency alters brain development in mouse

Andrea L. Gompers, Linda Su-Feher, Jacob Ellegood, Nycole A. Copping, M. Asrafuzzaman Riyadh, Tyler W. Stradleigh, Michael C. Pride, Melanie D. Schaffler, A. Ayanna Wade, Rinaldo Catta-Preta, Iva Zdilar, Shreya Louis, Gaurav Kaushik, Brandon J. Mannion, Ingrid Plajzer-Frick, Veena Afzal, Axel Visel, Len A. Pennacchio, Diane E. Dickel, Jason P. LerchJacqueline Crawley, Konstantinos Zarbalis, Jill L Silverman, Alexander Nord

Research output: Contribution to journalArticle

57 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1062-1073
Number of pages12
JournalNature Neuroscience
Volume20
Issue number8
DOIs
StatePublished - Aug 1 2017

ASJC Scopus subject areas

  • Neuroscience(all)

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    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., ... Nord, A. (2017). Germline Chd8 haploinsufficiency alters brain development in mouse. Nature Neuroscience, 20(8), 1062-1073. https://doi.org/10.1038/nn.4592