Germline Chd8 haploinsufficiency alters brain development in mouse.
Gompers AL., Su-Feher L., Ellegood J., Copping NA., Riyadh MA., Stradleigh TW., Pride MC., Schaffler MD., Wade AA., Catta-Preta R., Zdilar I., Louis S., Kaushik G., Mannion BJ., Plajzer-Frick I., Afzal V., Visel A., Pennacchio LA., Dickel DE., Lerch JP., Crawley JN., Zarbalis KS., Silverman JL., Nord AS.
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.