CHD8 mutations increase gliogenesis to enlarge brain size in the nonhuman primate

Author:

Li Bang,Zhao Hui,Tu Zhuchi,Yang Weili,Han Rui,Wang Lu,Luo Xiaopeng,Pan Mingtian,Chen Xiusheng,Zhang Jiawei,Xu Huijuan,Guo Xiangyu,Yan Sen,Yin Peng,Zhao Zhiguang,Liu Jianrong,Luo Yafeng,Li Yuefeng,Yang ZhengyiORCID,Zhang Baogui,Tan Zhiqiang,Xu Hao,Jiang Tianzi,Jiang Yong-hui,Li ShihuaORCID,Zhang Yong Q.,Li Xiao-JiangORCID

Abstract

AbstractAutism spectrum disorder (ASD) is a complex neurodevelopmental condition that affects social interaction and behavior. Mutations in the gene encoding chromodomain helicase DNA-binding protein 8 (CHD8) lead to autism symptoms and macrocephaly by a haploinsufficiency mechanism. However, studies of small animal models showed inconsistent findings about the mechanisms for CHD8 deficiency-mediated autism symptoms and macrocephaly. Using the nonhuman primate as a model system, we found that CRISPR/Cas9-mediated CHD8 mutations in the embryos of cynomolgus monkeys led to increased gliogenesis to cause macrocephaly in cynomolgus monkeys. Disrupting CHD8 in the fetal monkey brain prior to gliogenesis increased the number of glial cells in newborn monkeys. Moreover, knocking down CHD8 via CRISPR/Cas9 in organotypic monkey brain slices from newborn monkeys also enhanced the proliferation of glial cells. Our findings suggest that gliogenesis is critical for brain size in primates and that abnormal gliogenesis may contribute to ASD.

Publisher

Springer Science and Business Media LLC

Subject

Cell Biology,Genetics,Molecular Biology,Biochemistry

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