Wdr62 in neural development and malformations of cortical development disease

描述（由申请人提供）：皮质发育畸形（MCD）是发育障碍的主要原因，也是许多神经系统疾病的根源。虽然人类遗传学研究已经建立了一类中心体蛋白和MCD之间的联系，这些蛋白的体内功能和MCD疾病的病理生理机制仍然不清楚。聚焦于一个MCD疾病相关基因Wdr62，它编码一个中心体蛋白，这个建议的目标是确定在正常皮质发育过程中的Wdr62在体内的作用和功能机制，并调查Wdr62突变如何导致广泛的MCD疾病。在未来五年内提出了三个具体目标。第一个是使用小鼠遗传学方法来确定Wdr62在正常皮质发育中的发育和细胞功能。第二个是测试在体外和体内的作用，个别Wdr62疾病相关的突变在皮质发育。我的最后一个目标是开发一种新的亲和纯化方法，以确定从发育中的小鼠大脑中介导WDR 62功能的调节因子。这些研究将推动该领域的发展，不仅为Wdr62的生理功能和作用机制提供了新的见解，而且还为阐明MCD疾病的病因提供了基础知识。

DESCRIPTION (provided by applicant): Malformations of cortical development (MCD) represent a major cause of developmental disabilities and are at the root of numerous neurological disorders. Although human genetic studies have established a link between a class of centrosome proteins and MCD, the in vivo functions of these proteins and the pathophysiological mechanisms of MCD diseases remain obscure. Focusing on one MCD disease-associated gene Wdr62, which encodes a centrosome protein, the goals of this proposal are to determine the in vivo roles and functional mechanisms of Wdr62 during normal cortical development and to investigate how Wdr62 mutations lead to a wide spectrum of MCD disorders. Three specific aims are proposed over the next 5 years. The first is to use mouse genetic approaches to determine the developmental and cellular functions of Wdr62 in normal cortical development. The second is to test the in vitro and in vivo roles of individual Wdr62 disease-associated mutations during cortical development. My last aim is to develop a new affinity purification method to identify the regulators that mediate WDR62 functions from developing mouse brains. These studies will advance the field not only by providing novel insights into the physiological functions and mechanisms of action of Wdr62, but also by contributing fundamental knowledge to elucidate the etiologies of MCD diseases.