Wdr62 in neural development and malformations of cortical development disease

描述（由申请人提供）：皮层发育畸形（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与MCD之间的联系，但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。本研究以MCD相关基因Wdr62为研究对象，该基因编码一种中心体蛋白，目的是确定Wdr62在正常皮质发育过程中的体内作用和功能机制，并研究Wdr62突变如何导致广泛的MCD疾病。提出了未来5年的三个具体目标。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。第二个是测试个体Wdr62疾病相关突变在皮质发育过程中的体外和体内作用。我的最后一个目标是开发一种新的亲和纯化方法来鉴定发育中的小鼠大脑中介导WDR62功能的调节因子。这些研究不仅为Wdr62的生理功能和作用机制提供了新的见解，而且为阐明MCD疾病的病因提供了基础知识，将推动该领域的发展。

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.