The autism-associated protein CHD8 is required for cerebellar development and motor function
The autism-associated protein CHD8 is required for cerebellar development and motor function
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DOI：
10.1016/j.celrep.2021.108932
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发表时间：
2021-04-06
期刊：
影响因子：
8.8
通讯作者：
Nakayama, Keiichi, I
中科院分区：
文献类型：
--
作者：
Kawamura, Atsuki;Katayama, Yuta;Nakayama, Keiichi, I
编码染色质重塑器染色体结构解旋酶dna结合蛋白8 （CHD8）的基因突变是自闭症谱系障碍（ASD）的高渗透危险因素。尽管小脑异常一直被认为与ASD的发病机制有关，但小脑CHD8功能障碍是否与ASD表型有关仍是一个很大的未知数。我们在这里表明，小鼠小脑颗粒神经元祖细胞（GNP）特异性缺失Chd8会损害这些细胞的增殖和分化，并导致小脑发育不全和运动协调缺陷，但不会导致asd样行为异常。CHD8被发现调节GNPs中神经元基因的表达。它还优先结合到启动子区域，并调节这些细胞中转录活性基因的局部染色质可及性。因此，我们的研究结果揭示了CHD8在小脑发育中的关键作用，对理解这一大脑区域对ASD发病机制的贡献具有重要意义。
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.