Wdr62 in neural development and malformations of cortical development disease

摘要：皮质发育畸形(MCD)是发育障碍的主要原因之一。 残疾，是许多神经疾病的根源。尽管人类基因研究已经 建立了一类中心体蛋白与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尚不清楚。专注于一种MCD疾病- 相关基因Wdr62，它编码中心体蛋白，这项提议的目的是确定在 Wdr62在正常大脑皮质发育过程中的作用和作用机制 Wdr62突变导致一系列MCD疾病。在接下来的5年里，我们提出了三个具体目标 好几年了。第一个是使用小鼠遗传学方法来确定人的发育和细胞功能 Wdr62，皮质发育正常。第二个是测试单个Wdr62在体外和体内的作用 皮质发育过程中与疾病相关的突变。我的最后一个目标是开发一种新的亲和纯化 方法从发育中的小鼠大脑中确定介导WDR62功能的调节因子。这些研究 将不仅通过提供对生理功能和机制的新见解来推动该领域的发展 Wdr62的作用，也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.