Article abstract
Nature Neuroscience 12, 1398 - 1406 (2009)
Published online: 18 October 2009 | doi:10.1038/nn.2410
The oligodendrocyte-specific G protein–coupled receptor GPR17 is a cell-intrinsic timer of myelination
Ying Chen1, Heng Wu1, Shuzong Wang1, Hisami Koito2, Jianrong Li2, Feng Ye1, Jenny Hoang1, Sabine S Escobar3, Alexander Gow4, Heather A Arnett3, Bruce D Trapp5, Nitin J Karandikar6, Jenny Hsieh7 & Q Richard Lu1,6,7
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.
- Department of Developmental Biology and Kent Waldrep Foundation Center for Basic Neuroscience Research on Nerve Growth and Regeneration, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
- Department of Veterinary Integrative Biosciences, Texas A&M University, College Station, Texas, USA.
- Department of Inflammation, Amgen, Seattle, Washington, USA.
- Center for Molecular Medicine and Genetics, Wayne State University, Detroit, Michigan, USA.
- Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.
- Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
- Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Correspondence to: Q Richard Lu1,6,7 e-mail: qrichard.lu@utsouthwestern.edu
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