The oligodendrocyte-specific G protein-coupled receptor GPR17 is a cell-intrinsic timer of myelination.
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.
Ying
Y
Chen
Heng
H
Wu
Shuzong
S
Wang
Hisami
H
Koito
Jianrong
J
Li
Feng
F
Ye
Jenny
J
Hoang
Sabine S
SS
Escobar
Alexander
A
Gow
Heather A
HA
Arnett
Bruce D
BD
Trapp
Nitin J
NJ
Karandikar
Jenny
J
Hsieh
Q Richard
QR
Lu
D000818:Animals; D001921:Brain / Q000166:cytology; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation / Q000379:methods; D003711:Demyelinating Diseases / Q000378:metabolism* / Q000503:physiopathology*; D004195:Disease Models, Animal; D004622:Embryo, Mammalian; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000473:pathology / Q000503:physiopathology; D005260:Female; D049452:Green Fluorescent Proteins / Q000235:genetics; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009103:Multiple Sclerosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000502:physiology*; D009836:Oligodendroglia; D009900:Optic Nerve / Q000166:cytology; D051381:Rats; D011916:Rats, Inbred F344; D043562:Receptors, G-Protein-Coupled / Q000172:deficiency / Q000502:physiology*; D013116:Spinal Cord / Q000166:cytology; D013234:Stem Cells; D013997:Time Factors; D014162:Transfection / Q000379:methods
C534979:GPR17 protein, mouse; D009419:Nerve Tissue Proteins; D043562:Receptors, G-Protein-Coupled; D049452:Green Fluorescent Proteins