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.

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Figure 1: Identification and expression of Gpr17 in the murine CNS.
Figure 2: Transient expression of Gpr17 in oligodendrocytes during development.
Figure 3: Deficient Mbp expression in the brain of Gpr17 transgenic mice.
Figure 4: Myelinogenesis defects in the CNS of CNP-Gpr17 transgenic mice.
Figure 5: GPR17 overexpression inhibits oligodendrocyte differentiation and induces nuclear translocation of ID2 and 4.
Figure 6: Early onset of oligodendrocyte myelination in Gpr17−/− mice.

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Acknowledgements

We thank C. Stiles, J. Chan, J. Johnson, R. Bassel-Duby, E. Hurlock and T. Hu for critical comments; M. Gravel for the Cnp1 promoter; M. Yanagisawa for ligand analysis; J. Koch for preliminary injury study; J. Cai, T. Hu, X. Xu and T. Yue for technical assistance; L. Cai for microarray analysis; and T. Januszewski and L. Mueller for electron microscopy. This study was funded by grants from the US National Institutes of Health (NS050389 to Q.R.L. and NS060017 to J.L.) and the National Multiple Sclerosis Society (RG3978 to Q.R.L. and RG2891 to A.G.). Q.R.L. is a Harry Weaver Neuroscience Scholar.

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Q.R.L. designed the study, analyzed the data and coordinated the project. Y.C performed the analysis of transgenic and knockout mice and carried out the immunohistological and biochemical assays. H.W. generated Gpr17 knockout mice. S.W. performed the initial gene analysis and assisted with the generation of Gpr17 transgenic mice. H.K. and J.L. carried out OPC transfection and analysis. F.Y. and J. Hoang performed in situ hybridization and ChIP assays. S.S.E. and H.A.A. analyzed multiple sclerosis samples. A.G. carried out the cell death assay. B.D.T. analyzed multiple sclerosis samples and contributed conceptually to the project. N.J.K. provided EAE mice. J. Hsieh provided HCN cells and performed biochemical assays. Q.R.L. and Y.C. wrote the manuscript.

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Correspondence to Q Richard Lu.

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Chen, Y., Wu, H., Wang, S. et al. The oligodendrocyte-specific G protein–coupled receptor GPR17 is a cell-intrinsic timer of myelination. Nat Neurosci 12, 1398–1406 (2009). https://doi.org/10.1038/nn.2410

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