title: 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.
  
  
  
  Genome occupancy analysis of oligodendrocytes in response to lysolecithin-mediated demyelination injury revealed that Olig2 and its downstream target Gpr17 are part of regulatory circuitry critical for oligodendrocyte survival. Gpr17 inhibits oligodendrocyte survival through activation of Xaf1 and cell differentiation by reducing Epac1 expression. The loss of Gpr17 in mice led to precocious myelination and an earlier onset of remyelination after demyelination. Pharmacological inhibition of Gpr17 promoted remyelination, highlighting the potential for Gpr17-targeted therapeutic approaches in demyelination diseases.
authors.affiliation: State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen 361005, Fujian Province, China.
authors.forename: Zhimin
authors.initials: Z
authors.lastname: Ou
authors.affiliation: State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen 361005, Fujian Province, China.
authors.forename: Yuxia
authors.initials: Y
authors.lastname: Sun
authors.affiliation: State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen 361005, Fujian Province, China.
authors.forename: Li
authors.initials: L
authors.lastname: Lin
authors.affiliation: State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen 361005, Fujian Province, China.
authors.forename: Nachun
authors.initials: N
authors.lastname: You
authors.affiliation: State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen 361005, Fujian Province, China.
authors.forename: Xue
authors.initials: X
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen 361005, Fujian Province, China.
authors.forename: Hongchao
authors.identifier: 0000-0002-7979-5410
authors.initials: H
authors.lastname: Li
authors.affiliation: State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen 361005, Fujian Province, China.
authors.forename: Yanchen
authors.initials: Y
authors.lastname: Ma
authors.affiliation: State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen 361005, Fujian Province, China.
authors.forename: Lei
authors.identifier: 0000-0003-2728-3023
authors.initials: L
authors.lastname: Cao
authors.affiliation: The First Affiliated Hospital of Xiamen University, Xiamen 361101, Fujian Province, China, and.
authors.forename: Ying
authors.initials: Y
authors.lastname: Han
authors.affiliation: State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen 361005, Fujian Province, China.
authors.forename: Min
authors.identifier: 0000-0001-5183-1187
authors.initials: M
authors.lastname: Liu
authors.affiliation: Cancer and Blood Disease Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229.
authors.forename: Yaqi
authors.initials: Y
authors.lastname: Deng
authors.affiliation: State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen 361005, Fujian Province, China.
authors.forename: Luming
authors.initials: L
authors.lastname: Yao
authors.affiliation: Cancer and Blood Disease Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229.
authors.forename: Q Richard
authors.identifier: 0000-0001-6846-9014
authors.initials: QR
authors.lastname: Lu
authors.affiliation: State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen 361005, Fujian Province, China, yingchen@xmu.edu.cn.
authors.forename: Ying
authors.initials: Y
authors.lastname: Chen
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D051017:Apoptosis Regulatory Proteins; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics* / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects*; D002867:Chromones / Q000494:pharmacology; D002874:Chromosome Mapping; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000187:drug effects; D003711:Demyelinating Diseases / Q000139:chemically induced* / Q000473:pathology*; D044783:F-Box Proteins / Q000187:drug effects; D020662:Guanine Nucleotide Exchange Factors / Q000096:biosynthesis / Q000235:genetics; D020024:Leukotriene Antagonists / Q000494:pharmacology; D008244:Lysophosphatidylcholines / Q000633:toxicity*; D051379:Mice; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism*; D000076104:Oligodendrocyte Transcription Factor 2; D009836:Oligodendroglia / Q000187:drug effects*; D016760:Proto-Oncogene Proteins c-fos / Q000187:drug effects; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D051792:Basic Helix-Loop-Helix Proteins; D002867:Chromones; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D044783:F-Box Proteins; D020662:Guanine Nucleotide Exchange Factors; D020024:Leukotriene Antagonists; D008244:Lysophosphatidylcholines; D009419:Nerve Tissue Proteins; D000076104:Oligodendrocyte Transcription Factor 2; D016760:Proto-Oncogene Proteins c-fos; D043562:Receptors, G-Protein-Coupled; C482601:Epac protein, mouse; C534979:GPR17 protein, mouse; C512773:Olig2 protein, mouse; C528956:XAF1 protein, mouse; C047681:pranlukast
keywords: Gpr17; apoptosis; oligodendrocytes; remyelination