Orphan G protein-coupled receptor GPR56 regulates neural progenitor cell migration via a Gα12/13 and rho pathway
Orphan G protein-coupled receptor GPR56 regulates neural progenitor cell migration via a Gα12/13 and rho pathway
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DOI：
10.1074/jbc.m708919200
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发表时间：
2008-05-23
影响因子：
4.8
通讯作者：
Itoh, Hiroshi
中科院分区：
文献类型：
--
作者：
Iguchi, Tokuichi;Sakata, Kensei;Itoh, Hiroshi
在前脑发育过程中，神经前体细胞（NPCs）的迁移和定位受到多种分子的协调调节。因此，这些分子的突变会导致皮质畸形。据报道，GPR 56是一种皮质畸形相关基因，在双侧额顶叶多微脑回患者中发生突变。GPR 56编码孤儿G蛋白偶联受体，其突变会降低细胞表面表达。也有报道称，GPR 56的表达水平参与癌细胞粘附和转移。然而，GPR 56如何在大脑发育中发挥作用以及哪些信号通路被GPR 56激活仍有待澄清。在这项研究中，我们发现GPR 56在NPC中高度表达，并具有抑制NPC迁移的能力。我们发现GPR 56与G α（12/13）偶联并诱导Rho依赖的转录激活，其通过血清响应元件和NF-κ B响应元件以及肌动蛋白纤维重组介导。p115 Rho特异性鸟嘌呤核苷酸交换因子（p115 RhoGEF RGS）的RGS结构域和显性负性形式的Rho抑制转录激活和肌动蛋白重组。此外，我们已经证明了具有激动活性的功能性抗GPR 56抗体抑制NPC迁移。p115 RhoGEF RGS、C3外切酶和GPR 56敲低可减弱这种抑制作用。这些结果表明GPR 56通过G α（12/13）和Rho信号通路参与NPC运动的调控，提示其在中枢神经系统发育中的重要作用。
In the developing forebrain, the migration and positioning of neural progenitor cells (NPCs) are regulated coordinately by various molecules. Mutation of these 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 receptor, 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. However, it remains to be clarified how GPR56 functions in brain development and which signaling pathways are activated by GPR56. In this study, we showed that GPR56 is highly expressed in NPCs and has the ability to inhibit NPC migration. We found that GPR56 coupled with G alpha(12/13) and induced Rho-dependent activation of the transcription mediated through a serum-responsive element and NF-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, we have demonstrated that a functional anti-GPR56 antibody, which has an agonistic activity, inhibited NPC migration. This inhibition was attenuated by p115 RhoGEF RGS, C3 exoenzyme, and GPR56 knockdown. These results indicate that GPR56 participates in the regulation of NPC movement through the G alpha(12/13) and Rho signaling pathway, suggesting its important role in the development of the central nervous system.