神经发育相关疾病是一类由于中枢神经系统发育缺陷导致的疾病，包含多种亚型，且均严重影响患者及其家属的生活。由于其极高的遗传异质性，鉴定准确病因困难，发病机制不清，更加缺乏有效的早期干预或治疗手段。因而相关研究是本领域的难点及热点问题。近年来，通过对大量患者的基因组学研究，WAC基因的突变已被证实与发育迟滞、智力障碍及孤独症等神经系统发育疾病相关。目前对其分子功能的研究主要是在非神经系统中进行的，已有发现包括其参与调节某些蛋白的泛素化水平及自噬通路的活性等。而WAC在神经系统发育过程中的作用，WAC突变影响到哪些神经环路，WAC作用于神经系统的分子机制等一系列问题均不明了。本项目拟针对WAC导致神经系统疾病的发病机制展开研究，采用斑马鱼为模式生物，构建功能缺失型突变体研究WAC基因在神经系统发育、动物行为及神经环路激活等过程中的作用，从而帮助阐明Wac基因突变导致相关疾病发生的分子机制。

Neurodevelopmental disorders are caused by impairment of the development of the central nervous system, which could largely attenuate the intellectual and social abilities of the patients. Due to their extremely high genetic heterogeneity, it is quite challenging to identify the genetic causes of the diseases and to study the underlying molecular mechanisms. Recently years, large scale next-generation sequencing studies have promoted the identification of many novel neurodevelopmental disease genes, including WAC. The association between WAC mutations and several forms of neurodevelopmental diseases have been reported by many independent studies. However, it remains unclear how mutations in WAC cause these diseases. Previous studies have shown that WAC is involved in regulating ubiquitination of certain target proteins such as H2B, as well as in regulating autophagy pathways. However, whether these functions are related to the disease pathology remains unclear. In this study, we propose to use Zebrafish as a model system to study the function of WAC in neurodevelopment, animal behavior and neuronal circuit function. These findings may shed light on the molecular pathology underlying the neurodevelopmental disorders caused by WAC mutations.