Adhesion G protein-coupled receptors in CNS development and regeneration

 描述(申请人提供)：髓鞘是由神经胶质细胞产生的多层膜，用于隔离和保护脊椎动物神经系统中的轴突。在中枢神经系统(CNS)，少突胶质细胞(OL)形成髓鞘。控制少突胶质细胞发育、髓鞘形成和髓鞘修复的分子机制尚不清楚；髓鞘在许多神经系统疾病中被破坏，因此更好地了解OL生物学具有重要的临床意义。这项建议的目的是研究黏附G蛋白偶联受体GPR56如何调节OL的发育、髓鞘形成和髓鞘修复。GPR56基因突变会导致一种毁灭性的人类大脑畸形，称为双侧额顶顶叶多微回(BFPP)，在这种畸形中，大脑的正常皮质皱折被许多小脑回取代。除了大脑皮层形成不良外，BFPP患者的脑白质也受到不利影响。BFPP脑的MRI图像显示信号变化，表明髓鞘缺陷。此外，我们的初步研究表明：1)GPR56在少突胶质前体细胞(OPC)和未成熟的OPC中表达；2)GPR56的缺失导致小鼠中枢神经系统髓鞘缺陷；3)在CNS中存在一个新的GPR56配体。综上所述，我们的数据支持这样的假设，即GPR56是以前未被认识的中枢神经系统髓鞘形成的调节因子。这项提议旨在检验这一假说，从而建立神经胶质细胞发育和髓鞘形成的新调节机制。我们的工作可能会增强对髓鞘形成的基本生物学的理解，并可能揭示促进髓鞘疾病修复的治疗新靶点。

 DESCRIPTION (provided by applicant): Myelin is the multilayered membrane generated by glial cells that insulates and protects axons in the vertebrate nervous system. In the central nervous system (CNS), oligodendrocytes (OLs) form the myelin sheath. The molecular mechanisms that govern oligodendrocyte development, myelination, and myelin repair are poorly understood; myelin is disrupted in many neurological diseases, and so a better understanding of OL biology has important clinical implications. The object of this proposal is to study how the adhesion G protein- coupled receptor GPR56 regulates OL development, myelination, and myelin repair. Mutations in GPR56 cause a devastating human brain malformation called bilateral frontoparietal polymicrogyria (BFPP), in which the normal cortical folds of the cerebrum are replaced by numerous small gyri. In addition to the poor formation of the cerebral cortex, white matter is also adversely affected in BFPP patients. MRI images of BFPP brains reveal signal changes indicating myelination defects. Furthermore, our preliminary studies demonstrate that: 1) GPR56 is expressed in oligodendrocyte progenitor cells (OPCs) and immature OLs; 2) disruption of Gpr56 leads to CNS myelin defects in mice; and 3) there is a novel putative ligand of GPR56 in CNS. Taken together, our data support the hypothesis that GPR56 is a previously unappreciated regulator of myelination in the CNS. This proposal is designed to test this hypothesis, thus establishing novel regulators of glial cell development and myelination. Our work is likely to enhance the understanding of the basic biology of myelination and will potentially reveal a new target for therapeutics to promote repair in myelin disease.