The autism-associated protein CHD8 is required for cerebellar development and motor function

Mutations in the gene encoding the chromatin remodeler chromodomain helicase DNA-binding protein 8 (CHD8) are a highly penetrant risk factor for autism spectrum disorder (ASD). Although cerebellar abnormalities have long been thought to be related to ASD pathogenesis, it has remained largely unknown whether dysfunction of CHD8 in the cerebellum contributes to ASD phenotypes. We here show that cerebellar granule neuron progenitor (GNP)-specific deletion of Chd8 in mice impairs the proliferation and differentiation of these cells as well as gives rise to cerebellar hypoplasia and a motor coordination defect, but not to ASD-like behavioral abnormalities. CHD8 is found to regulate the expression of neuronal genes in GNPs. It also binds preferentially to promoter regions and modulates local chromatin accessibility of transcriptionally active genes in these cells. Our results have thus uncovered a key role for CHD8 in cerebellar development, with important implications for understanding the contribution of this brain region to ASD pathogenesis. [Display omitted] •CHD8 ablation in the brain of mice results in cerebellar hypoplasia•CHD8 regulates proliferation and differentiation of granule neuron progenitors (GNPs)•CHD8 loss in GNPs results in a motor function defect, but not in autism-like behavior•CHD8 is essential for the activation of neuronal gene expression in GNPs Kawamura et al. reveal that CHD8 regulates the expression of many synapse- and cerebellar-granule-neuron-related genes and thereby promotes the development of granule neuron progenitors (GNPs). CHD8 ablation in GNPs impairs the proliferation, differentiation, and synapse function of these cells and results in cerebellar hypoplasia and motor coordination defects.