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The oligodendrocyte-specific G protein-coupled receptor GPR17 is a cell-intrinsic timer of myelination.

ABSTRACT: The basic helix-loop-helix transcription factor Olig1 promotes oligodendrocyte maturation and is required for myelin repair. We characterized an Olig1-regulated G protein-coupled receptor, GPR17, whose function is to oppose the action of Olig1. Gpr17 was restricted to oligodendrocyte lineage cells, but was downregulated during the peak period of myelination and in adulthood. Transgenic mice with sustained Gpr17 expression in oligodendrocytes exhibited stereotypic features of myelinating disorders in the CNS. Gpr17 overexpression inhibited oligodendrocyte differentiation and maturation both in vivo and in vitro. Conversely, Gpr17 knockout mice showed early onset of oligodendrocyte myelination. The opposing action of Gpr17 on oligodendrocyte maturation reflects, at least partially, upregulation and nuclear translocation of the potent oligodendrocyte differentiation inhibitors ID2/4. Collectively, these findings suggest that GPR17 orchestrates the transition between immature and myelinating oligodendrocytes via an ID protein-mediated negative regulation and may serve as a potential therapeutic target for CNS myelin repair.

SUBMITTER: Chen Y

PROVIDER: S-EPMC2783566 | biostudies-literature | 2009 Nov

REPOSITORIES: biostudies-literature

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The oligodendrocyte-specific G protein-coupled receptor GPR17 is a cell-intrinsic timer of myelination.

Chen Ying Y Wu Heng H Wang Shuzong S Koito Hisami H Li Jianrong J Ye Feng F Hoang Jenny J Escobar Sabine S SS Gow Alexander A Arnett Heather A HA Trapp Bruce D BD Karandikar Nitin J NJ Hsieh Jenny J Lu Q Richard QR

Nature neuroscience 20091018 11

The basic helix-loop-helix transcription factor Olig1 promotes oligodendrocyte maturation and is required for myelin repair. We characterized an Olig1-regulated G protein-coupled receptor, GPR17, whose function is to oppose the action of Olig1. Gpr17 was restricted to oligodendrocyte lineage cells, but was downregulated during the peak period of myelination and in adulthood. Transgenic mice with sustained Gpr17 expression in oligodendrocytes exhibited stereotypic features of myelinating disorder ...[more]

PMID: 19838178

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Project description: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.Significance statementGenome 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.

Dataset Information

The oligodendrocyte-specific G protein-coupled receptor GPR17 is a cell-intrinsic timer of myelination.

Publications

The oligodendrocyte-specific G protein-coupled receptor GPR17 is a cell-intrinsic timer of myelination.

Similar Datasets

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