| Budget Amount *help |
¥4,140,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥540,000)
Fiscal Year 2007: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
Fiscal Year 2006: ¥1,800,000 (Direct Cost: ¥1,800,000)
|
|---|
| Research Abstract |
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.
|
