TY - JOUR T1 - Heterozygous mutation to <em>Chd8</em> causes macrocephaly and widespread alteration of neurodevelopmental transcriptional networks in mouse JF - bioRxiv DO - 10.1101/076158 SP - 076158 AU - Andrea L. Gompers AU - Linda Su-Feher AU - Jacob Ellegood AU - Tyler W. Stradleigh AU - Iva Zdilar AU - Nycole A. Copping AU - Michael C. Pride AU - Melanie D. Schaffler AU - M. Asrafuzzaman Riyadh AU - Gaurav Kaushik AU - Brandon Mannion AU - Ingrid Plajzer-Frick AU - Veena Afzal AU - Axel Visel AU - Len A. Pennacchio AU - Diane Dickel AU - Jason P. Lerch AU - Jacqueline N. Crawley AU - Konstantinos S. Zarbalis AU - Jill L. Silverman AU - Alex S. Nord Y1 - 2016/01/01 UR - http://biorxiv.org/content/early/2016/09/20/076158.abstract N2 - 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. ER -