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

Atsuki Kawamura, Yuta Katayama, Wataru Kakegawa, Daisuke Ino, Masaaki Nishiyama, Michisuke Yuzaki, Keiichi I. Nakayama

研究成果: Article査読

抄録

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.

本文言語English
論文番号108932
ジャーナルCell Reports
35
1
DOI
出版ステータスPublished - 2021 4 6

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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