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.

在发育中的脑皮质中，神经祖细胞（NPC）的迁移由各种分子协调调节。因此，它们的分子突变会导致皮质畸形。据报道，GPR56是一种皮质畸形相关的基因，在双侧额叶多发性多发性疾病患者中被突变。 GPR56编码孤儿G蛋白偶联受体，其突变减少了细胞表面表达。还报道了GPR56的表达水平参与癌细胞粘附和转移。 Howevet尚待澄清GPR56在大脑发育中的功能以及GPR56激活了哪些信号通路。我表明GPR56在NPC中高度表达，并且具有抑制NPC迁移的能力。我指出，GPR56与Gα12/13结合，并诱导通过血清反应元件和核因子-KAPPA B响应元件和肌动蛋白纤维重组介导的转录的Rho依赖性激活。转录激活和肌动蛋白的重组被P115 RHO特异性鸟嘌呤核交换因子（P115 Rhogef RGS）的RGS结构域抑制，RHO的主要负面形式。此外，我证明具有激动活性的功能性抗GPR56抗体抑制了NPC迁移。 P115 Rhogef RGS，C3 excenzyme和GPR56敲低减轻了这种抑制作用。这些结果表明，GPR56参与了通过Gα12/13和Rho信号通路对NPC运动的调节，这表明其在中枢神经系统的发展中的重要作用。以前，我还证明了GαQ/11-和JNK介导的信号抑制了NPC迁移，这表明独特的G蛋白信号调节了神经祖细胞的迁移。此外，GPR56的功能抗体预计将是分析脑发育脑疾病和肿瘤发生的有用工具。