The Autism-Associated Protein CHD8 Is Required for Cerebellar Development and Motor Function

Mutations in the gene encoding the chromatin remodeler CHD8 are a highly penetrant risk factor for autism spectrum disorder (ASD). Although cerebellar abnormalities have been involved in ASD pathogenesis, the underlying mechanisms of CHD8 in the regulation of cerebellar function has remained unknown, however. Here we show that the cerebellar granule neurons–specific deletion of Chd8 manifests reduced proliferation and differentiation of granule neuron progenitors, leading to cerebellar hypoplasia and motor coordination defects in mice. CHD8 was found to regulate the expression of neuronal genes and to be required for maturation of cerebellar granule neurons. Furthermore, we found that CHD8 is preferentially bound to promoter regions and is necessary for modulation of local chromatin accessibilities at promoter regions of active gene. Our results thus uncover a critical role for CHD8 in cerebellar development and have important implications for understanding the cerebellar contributions to ASD pathogenesis. Overall design: RNA-seq (quadruplicate) and ChIP-seq (duplicate) analysis in granule neuron progenitors (GNPs) isolated from the cerebellum of mice at P7