脑部过度增生常见于自闭症，可能由过度神经发生所致。自闭症高风险基因CHD8编码染色质异构蛋白，其突变患者近80%伴随巨脑畸形。我们发现敲减Chd8导致斑马鱼脑部增大，局部脑区神经元过量增加，相应脑区中beta-catenin通路分子过量上升继而下降，有强时序性。已知Chd8体外调节beta-catenin，我们推测，Chd8可能通过时序性调控beta-catenin通路，而调节神经发生和环路构建；前人关于Chd8的作用和机制看似“相悖”，可能缘于研究时段不同。我们将检验这一假设，系统研究Chd8在调控beta-catenin通路和神经发生中的时序性作用；探究过度神经发生对神经元递质类型和环路连接发育的影响；探索Chd8在斑马鱼行为中的作用。明晰Chd8在神经发生中的作用及其分子、细胞和环路机制，将有助于阐明过度神经发生在自闭症发病中的作用和机制，为自闭症的诊断和治疗提供实验支持。

Brain overgrowth is a common sign of autism and might be attributable to excess neurogenesis. CHD8 is a high-confidence autism risk gene encoding a chromatin remodeling protein. Almost 80% of the patients carrying CHD8 mutations present with macrocephaly. We found that knocking down Chd8 in zebrafish caused macrocephaly and overproduction of neurons in local brain regions. Intriguingly, the beta-catenin signaling molecules showed sequentially ectopic expression in the corresponding brain regions. It has been shown that Chd8 could regulate the beta-catenin signaling in vitro. We hypothesize that Chd8 participates neurogenesis through sequentially regulating the beta-catenin signaling and the seemingly "controversial" role of Chd8 in neurogenesis by previous studies could be due to the different developmental stage during which the studies were performed. In the present proposal, we will test the hypothesis by systematically investigating the timing role of Chd8 in regulating the beta-catenin signaling and neurogenesis; studying the role of Chd8 in neuronal type differentiation and neural circuit establishment; exploring the role of Chd8 in zebrafish behaviors. Elucidating the role and mechanism of Chd8 in excess neurogenesis at molecular, cellular and circuit levels will be helpful for us to reveal the pathogenesis of autism. The study will provide research basis and potential targets for the treatment and diagnosis of autism.