Wdr62 in neural development and malformations of cortical development disease

摘要：皮质发育畸形（MCD）是发育不良的主要原因之一。 残疾，是许多神经系统疾病的根源。尽管人类基因研究 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， MCD疾病的病理生理机制仍然不清楚。专注于一种MCD疾病- 相关基因Wdr 62，它编码一个中心体蛋白，这项建议的目标是确定在基因组中， Wdr 62在正常皮质发育过程中的体内作用和功能机制，并研究其如何 Wdr 62突变导致广泛的MCD疾病。在未来5年内提出了三个具体目标 年第一个是使用小鼠遗传学方法来确定发育和细胞功能， 正常皮质发育中的Wdr 62。第二是测试单个Wdr 62的体外和体内作用 在皮质发育过程中的疾病相关突变。我最后的目标是开发一种新的亲和纯化 方法来鉴定调节WDR 62功能的调控因子，从发育中的小鼠大脑。这些研究 将推进该领域不仅提供新的见解的生理功能和机制， Wdr 62的作用，而且还通过贡献基础知识来阐明MCD疾病的病因。

ABSTRACT: 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.