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中的调控基因突变经常与人类神经疾病有关。神经细胞增殖、迁移和分层的障碍尤其会导致智力低下和癫痫。我们的长期目标是研究皮质发育及其相关神经疾病的分子机制。通过位置克隆，我们最近证明了孤儿G蛋白偶联受体(GPCR)GPR56功能缺失突变会导致一种特殊的皮质畸形，称为双侧额顶顶叶多小脑回(BFPP)。发现GPR56是BFPP的致病基因，从而提出了GPR56信号通路在调节大脑皮质发育中起关键作用的具体假说。我们的假说基于已发表的初步观察结果，即：(1)GPR56基因突变导致一种特定的人类皮质畸形BFPP；(2)小鼠Gpr56 mRNA主要在神经元前体细胞中表达，表明它可能在皮层的发育和图案形成中发挥重要作用；(3)Gpr56基因敲除会导致小鼠皮质发育不良；(4)GPR56与13整合素和Gpr56/13整合素协同作用可使小鼠出现更严重和广泛的皮质发育不良。基于这些观察，这项建议的实验重点是GPR56在小鼠模型中的功能分析。其具体目的是：(1)阐明BFPP的发病机制；(2)研究GPR56和13整合素的潜在相互作用；(3)研究GPR56蛋白的运输。

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.