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调控基因的突变通常与人类神经系统疾病相关。神经元细胞增殖、迁移和分层的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。使用定位克隆，我们最近证明，GPR 56，孤儿G蛋白偶联受体（GPCR）的功能缺失突变，导致一个特定的皮质畸形称为双侧额顶叶多微脑回（BFPP）。GPR 56作为BFPP的致病基因的鉴定导致本申请的特定假设，即GPR 56的信号传导途径在调节皮质发育中是至关重要的。我们的假设是基于已发表的和初步的观察结果：（1）GPR 56突变导致特定的人类皮质畸形，BFPP;（2）小鼠Gpr 56 mRNA主要在神经元祖细胞中表达，表明它可能在皮质发育和图案化中起重要作用;（3）Gpr 56敲除导致小鼠皮质发育不良;（4）GPR 56与13整合素具有协同作用，Gpr 56/13整合素双敲除小鼠具有更严重和广泛的皮质发育不良。基于这些观察结果，本提案的实验重点是在小鼠模型中对GPR 56进行功能分析。具体目标是：（1）阐明BFPP的发病机制;（2）研究GPR 56和13整合素的潜在相互作用;（3）研究GPR 56蛋白的转运。

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.