Abstract
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.
Highlights
Autism spectrum disorder (ASD) is a neurodevelopmental disorder defined primarily by deficits in social interaction and communication as well as by restricted and repetitive behaviors
Our findings suggest that chromodomain helicase DNA-binding protein 8 (CHD8) is essential for cerebellar development and that CHD8 haploinsufficiency in the cerebellum might contribute to certain phenotypes of autism spectrum disorder (ASD) patients with CHD8 mutations, but not to their behavioral abnormalities
Nestin-Cre/Chd8LF/F mice were born in approximately the expected Mendelian ratio, these animals subsequently manifested growth retardation and a reduced body weight compared with control littermates, and most of them died before 3 weeks of age (Figures 1C–1E)
Summary
Autism spectrum disorder (ASD) is a neurodevelopmental disorder defined primarily by deficits in social interaction and communication as well as by restricted and repetitive behaviors. Studies with mouse models of ASD have shown that dysfunction of Purkinje cells or the right crus I region of the cerebellum is sufficient to confer ASDlike behaviors (Tsai et al, 2012; Ha et al, 2016; Peter et al, 2016; Stoodley et al, 2017). We recently found that CHD8 haploinsufficiency in oligodendrocytes results in myelination defects and recapitulates certain behavioral phenotypes of Chd heterozygous mutant mice (Kawamura et al, 2020). These various observations highlight the functional importance of CHD8 in brain development and ASD pathogenesis, the specific brain region in which CHD8 dysfunction gives rise to ASD development has been unclear
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