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.

GPR17 is an Essential Component of the Negative Feedback Loop of the Sonic Hedgehog Signalling Pathway in Neural Tube Development

“…Znf488 (also known as Zfp488), which is expressed in the same regions as Olig2 [29,30], did not have a significant effect on GPR17 expression (Fig 1E, lanes 1 and 4). These data supported the idea that GPR17 expression is targeted by Olig2 [28], and becomes exclusive to the floor plate as development progresses.…”

“…Next we explored the upstream transcription factors that induce GPR17 expression. Since GPR17 requires Olig1 for its expression [27] and is one of the target genes of Olig2 during oligodendrocyte development [28], we assessed if the overexpression of an Olig-type transcription factors could induce the GPR17 transcript. To address this, we prepared intermediate neural explants that were electroporated with the Olig2 expression plasmid, and determined the GPR17 expression level by RT-qPCR.…”

Developmental trajectory of oligodendrocyte progenitor cells in the human brain revealed by single cell RNA sequencing

“…Additional upregulated local networks identified in l‐OPCs included genes encoding cell–cell adhesion proteins, including neuroligins and neurexins (NLGN4X, NRXN1) and their interacting partner the leucine‐rich repeat transmembrane protein LRRTM1 (Reissner, Runkel, & Missler, ). Further, we detected upregulation of local networks associated with leukotriene signaling, implicated in OL survival (Ou et al, ), including the receptor GPR17, and glutamate signaling, including metabatropic receptor GRM5, and AMPA type glutamate receptor subunits, GRIA2 and GRIA3, implicated in OPC maturation and functional diversification during development (Deng, Wang, Rosenberg, Volpe, & Jensen, ; Luyt, Varadi, Durant, & Molnar, ; Spitzer et al, ).…”

Drug discovery for remyelination and treatment of MS

“…Expression analysis indicated that GPR17 was largely restricted to the oligodendrocyte lineage, and it was found that overexpression of GPR17 inhibited oligodendrocyte differentiation, whereas its abrogation accelerated oligodendrocyte differentiation and thus myelination (Chen et al, ). Importantly, a recent study indicated that pharmacological inhibition of GPR17 using pranlukast accelerated oligodendrocyte differentiation following toxin‐mediated demyelination, as did genetic abrogation of GPR17 (Ou et al, ). However, pranlukast does not specifically act on GPR17 (Grossman et al, ), but identification of a specific antagonist of GPR17 may represent a viable therapeutic option for enhancement of remyelination in the future.…”