Heterozygous mutation to Chd8 causes macrocephaly and widespread alteration of neurodevelopmental transcriptional networks in mouse

Abstract

The chromatin remodeling gene CHD8 represents a central node in early neurodevelopmental gene networks implicated in autism. We examined the impact of heterozygous germline Chd8 mutation on neurodevelopment in mice. Network analysis of neurodevelopmental gene expression revealed subtle yet strongly significant widespread transcriptional changes in Chd8+/- mice across autism-relevant networks from neurogenesis to synapse function. Chd8+/- expression signatures included enrichment of RNA processing genes and a Chd8-regulated module featuring altered transcription of chromatin remodeling, splicing, and cell cycle genes. Chd8+/- mice exhibited increased proliferation during brain development and neonatal increase in cortical length and volume. Structural MRI confirmed regional brain volume increase in adult Chd8+/- mice, consistent with clinical macrocephaly. Adult Chd8+/- mice displayed normal social interactions, and repetitive behaviors were not evident. Our results show that Chd8+/- mice exhibit neurodevelopmental changes paralleling CHD8+/- humans and show that Chd8 is a global genomic regulator of pathways disrupted in neurodevelopmental disorders.