GPR17在髓鞘损伤及再生过程中的作用

Myelin sheath is an essential structure to maintain the proper physiological function of nervous system. We previously reviewed that G-protein coupled receptor GPR17, which specifically expressed in the central nervous system, played an important role in oligodendrocytes development. Overexpression of GPR17 inhibited oligodendrocytes maturation and myelination. The high expression pattern of GPR17 in the Multiple Sclerosis lesions suggested it a potential regulator of demyelination. Our preliminary data showed that the expression of GPR17 was decreased in mature oligodendrocytes, but increased in drug induced demyelinating cells. Genome-wide ChIP-Seq analysis indicated that Olig2 regulated the transactivation of GPR17. In cuprizone-induced mouse demyelination model, the expression of GPR17 was up-regulated, and it might be subjected to the regulation of Olig2, as evidenced by a direct binding of Olig2 to the encoding region of GPR17 gene and a positive correlation between their gene expressions. Notably, GPR17 knockout mice were resistant to cuprizone-induced demyelination. According to our obtained results, various of in vitro and in vivo models will be further applied to investigate the interaction of Olig2 and GPR17 and their molecular basis on demyelination and remyelination, to shed a light on the intervention and prevention for demyelination disease in clinic.

髓鞘是维持神经系统正常生理功能的重要组成部分。我们先前工作发现G蛋白偶联受体GPR17特异性表达于中枢神经系统，在少突胶质细胞发育中具有重要调节作用。过表达GPR17抑制少突胶质细胞成熟与髓鞘形成，而在多样性硬化症病灶区的高表达提示GPR17是髓鞘损伤的潜在调节因子。前期实验证明：成熟少突胶质细胞中GPR17表达下降；而在药物诱导细胞损伤后GPR17表达明显上升。全基因组Chip-Seq结果显示转录因子Olig2调控GPR17的转录激活。在双环己酮草酰二腙（Cuprizone）诱导的脱髓鞘小鼠模型中，GPR17表达量增加，Olig2结合于GPR17编码区，并且其表达水平与GPR17呈正相关。在小鼠体内敲除GPR17显著抑制Cuprizone诱导的脱髓鞘进程。我们拟将利用多种细胞及动物模型深入研究GPR17与Olig2相互作用及调节髓鞘损伤再生的分子机制，为治疗和预防脱髓鞘疾病提供理论依据。

脱髓鞘疾病，如多发性硬化症等，是一种由于髓鞘的急性或慢性损伤以及髓鞘修复障碍所引起的疾病。当前，我们对这种疾病的发病机理仍知之甚少。通过对 lysolecithin诱导损伤后的少突胶质细胞模型进行Chip-Seq分析，我们发现Olig2及其下游的Gpr17在调控少突胶质细胞凋亡的过程中具有重要作用。损伤后的少突胶质细胞中Olig2的表达水平显著升高，并结合与Gpr17的启动子区域，促进Gpr17基因表达。Gpr17基因的激活抑制了少突胶质细胞的存活。这一作用是通过其对细胞内的cAMP水平的调控以及诱导凋亡基因Xaf1的表达所引起。PKA信号通路以及转录因子c-fos在这一调控过程中具有重要的作用。同时，当细胞中Gpr17的表达水平受到抑制时，Epac1的表达水平升高并促进了少突胶质前体细胞的分化。在动物体内，Gpr17基因的缺失可使小鼠出现髓鞘早熟，而Gpr17拮抗剂Pranlukast则能够促进髓鞘的损伤后修复。我们的结果证实，Gpr17的表达水平受Olig2所调控，在少突胶质细胞受到损伤时表达水平增加；而抑制Gpr17的活性则能够促进少突胶质细胞的发育及髓鞘修复。