Olig2-targeted G-protein-coupled receptor Gpr17 regulates oligodendrocyte survival in response to lysolecithin-induced demyelination

Abstract

Demyelinating diseases, such as multiple sclerosis, are known to result from acute or chronic injury to the myelin sheath and inadequate remyelination; however, the underlying molecular mechanisms remain unclear. Here, we performed genome occupancy analysis by chromatin immunoprecipitation sequencing in oligodendrocytes in response to lysolecithin-induced injury and found that Olig2 and its downstream target Gpr17 are critical factors in regulating oligodendrocyte survival. After injury to oligodendrocytes, Olig2 was significantly upregulated and transcriptionally targeted the Gpr17 locus. Gpr17 activation inhibited oligodendrocyte survival by reducing the intracellular cAMP level and inducing expression of the pro-apoptotic gene Xaf1. The protein kinase A signaling pathway and the transcription factor c-Fos mediated the regulatory effects of Gpr17 in oligodendrocytes. We showed that Gpr17 inhibition elevated Epac1 expression and promoted oligodendrocyte differentiation. The loss of Gpr17, either globally or specifically in oligodendrocytes, led to an earlier onset of remyelination after myelin injury in mice. Similarly, pharmacological inhibition of Gpr17 with pranlukast promoted remyelination. Our findings indicate that Gpr17, an Olig2 transcriptional target, is activated after injury to oligodendrocytes and that targeted inhibition of Gpr17 promotes oligodendrocyte remyelination.