Regulation of Cortical Development by GPR56 Signaling

描述（由申请人提供）：发育中的中枢神经系统调控基因突变经常与人类神经系统疾病相关。神经细胞增殖、迁移和层压障碍尤其会导致智力迟钝和癫痫。我们的长期目标是研究皮层发育及其相关神经系统疾病的分子机制。通过定位克隆，我们最近证明了GPR56（一种孤儿G蛋白偶联受体（GPCR））的功能缺失突变会导致一种称为双侧额顶多小回症（BFPP）的特异性皮质畸形。GPR56作为BFPP的致病基因的鉴定导致了该应用的特定假设，即GPR56的信号通路在调节皮质发育中至关重要。我们的假设是基于已发表的和初步的观察结果：(1)GPR56的突变导致一种特定的人类皮质畸形，BFPP；(2)小鼠Gpr56 mRNA主要在神经元祖细胞中表达，提示其可能在皮质发育和图案化中发挥重要作用；(3)敲除Gpr56导致小鼠皮质发育不良；(4) GPR56与13整合素协同作用，GPR56 /13整合素双敲除小鼠的皮质发育异常更为严重和广泛。基于以上观察结果，本课题的实验重点是GPR56在小鼠模型中的功能分析。具体目的是：(1)阐明BFPP的发病机制；(2)研究GPR56与13整合素的潜在相互作用；(3)研究GPR56蛋白的转运。大脑发育异常经常导致人类神经系统疾病，如智力迟钝和癫痫发作。基因GPR56在大脑发育中很重要，它的突变会导致人类大脑畸形。本研究旨在研究gpr56介导的脑发育及其相关病理生理。

DESCRIPTION (provided by applicant): Mutations of regulatory genes in the developing central nervous system are frequently associated with human neurological diseases. Disorders in neuronal cell proliferation, migration, and lamination, in particular, lead to mental retardation and epilepsy. Our long-term goal is to study the molecular mechanisms that underlie cortical development and their related neurological disorders. Using positional cloning, we recently demonstrated that loss-of-function mutation in GPR56, an orphan G protein-coupled receptor (GPCR), causes a specific cortical malformation known as bilateral frontoparietal polymicrogyria (BFPP). Identification of GPR56 as a causative gene of BFPP leads to the specific hypothesis of this application that the signaling pathway of GPR56 is crucial in regulating cortical development. Our hypothesis is based on published and preliminary observations that: (1) mutations in GPR56 cause a specific human cortical malformation, BFPP; (2) mouse Gpr56 mRNA is expressed mainly in neuronal progenitor cells, suggesting that it may play an important role in cortical development and patterning; and (3) Gpr56 knockout causes cortical dysplasia in mice; (4) GPR56 functions synergistically with 13 integrin and Gpr56/13 integrin double knockout mice have more severe and extensive cortical dysplasia. Based on these observations, the experimental focus of this proposal is on the functional analysis of GPR56 in mouse models. The specific aims are to: (1) delineate the pathogenesis of BFPP; (2) investigate the potential interaction of GPR56 and 13 integrin; and (3) study GPR56 protein trafficking. Abnormal brain development frequently causes human neurological disorders such as mental retardation and seizures. The gene GPR56 is important in brain development, and its mutation causes brain malformations in humans. The proposed research is designed to study GPR56-mediated brain development and its related pathophysiology.