Gprotein signaling in cortical development

皮质发育中的 G 蛋白信号传导

基本信息

批准号：
18590056
负责人：
MIZUNO Norikazu
金额：
$ 2.65万
依托单位：
Nara Institute of Science and Technology
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2006
资助国家：
日本
起止时间：
2006 至 2007
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18590056/
关键词：
signal transduction neuroscience brain neuron pharmacology

项目摘要

In the developing cerebral cortex, the migration of neural progenitor cells (NPCs) are coordinately regulated by various molecules. Mutation of them molecules, therefore, causes cortical malformation. GPR56 has been reported as a cortical malformation-related gene that is mutated in patients with bilateral frontoparietal polymicrogyria. GPR56 encodes an orphan G protein-coupled receptot and its mutations reduce the cell surface expression. It has also been reported that the expression level of GPR56 is involved in cancer cell adhesion and metastasis. Howevet it remains to be clarified how GPR56 functions in brain development and which signaling pathways are activated by GPR56. I showed that GPR56 is highly expressed in NPCs and has the ability to inhibit NPC migration. I indicated that GPR56 coupled with G α12/13 and induced Rho-dependent activation of the transcription mediated through a serum-responsive element and nuclear factor-kappa B-responsive element and actin fiber reorganization. The transcriptional activation and actin reorganization were inhibited by an RGS domain of the p115 Rho-specific guanine nucleotide exchange factor (p115 RhoGEF RGS) and dominant negative form of Rho. Moreover, I demonstrated that a functional anti-GPR56 antibody, which has an agonistic activity, inhibited NPC migration. This inhibition was attenuated by p115 RhoGEF RGS, C3 excenzyme, and GPR56 knockdown. These results indicated that GPR56 participates in the regulation of NPC movement through the G α12/13 and Rho signaling pathway, suggesting its important role in the development of the central nervous system. Previously, I have also demonstrated that the G αq/11- and JNK-mediated signals inhibited NPC migration, suggesting that the distinct G protein signals regulate the migration of neural progenitor cells. Moreover, the functional antibody of GPR56 is expected to be useful tool for analysis brain development brain disease, and tumorigenesis.

在大脑皮层的发育过程中，神经祖细胞（NPC）的迁移受到多种分子的协调调节，因此，GPR56被报道为一种在患有皮质畸形的患者中发生突变的基因。双侧额顶多小脑回编码孤儿G蛋白偶联受体，其突变降低了细胞表面表达水平。然而，GPR56 在大脑发育中的作用以及 GPR56 激活哪些信号通路仍有待澄清。我表明 GPR56 在 NPC 中表达，并且具有抑制 NPC 迁移的能力。 GPR56 与 G α12/13 偶联，诱导通过血清反应元件和核因子 kappa 介导的 Rho 依赖性转录激活B 响应元件和肌动蛋白纤维重组转录激活和肌动蛋白重组受到 p115 Rho 特异性鸟嘌呤核苷酸交换因子 (p115 RhoGEF RGS) 的 RGS 结构域和 Rho 的显性失活形式的抑制。具有激动活性的抗 GPR56 抗体可抑制 NPC 迁移，p115 RhoGEF RGS 可减弱这种抑制作用。 C3酶和GPR56敲低这些结果表明GPR56通过Gα12/13和Rho信号通路参与NPC运动的调节，表明其在中枢神经系统发育中的重要作用。 G αq/11 和 JNK 介导的信号抑制 NPC 迁移，表明独特的 G 蛋白信号调节神经祖细胞的迁移。此外，GPR56 的功能性抗体有望发挥作用。是分析大脑发育、脑疾病和肿瘤发生的有用工具。