CHD8 Mutations Increase Gliogenesis to Enlarge Brain Size in the Non-Human Primate
Bang Li, Hui Zhao, Zhuchi Tu, Weili Yang, Lu Wang, Rui Han, Xiaopeng Luo, Mingtian Pan, Xiusheng Chen, Jiawei Zhang, Huijuan Xu, Xiangyu Guo, Sen Yan, Zhiguang Zhao, Jianrong Liu, Yuefeng Li, Zhengyi Yang, Baogui Zhang, Zhiqiang Tan, Hao Xu, Tianzi Jiang, Yonghui Jiang, Shihua Li, Yong Q. Zhang, Xiao-Jiang Li
Autism 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.