TY - JOUR
T1 - Retinoid X receptor gamma signaling accelerates CNS remyelination
AU - Huang, Jeffrey K.
AU - Jarjour, Andrew A.
AU - Oumesmar, Brahim Nait
AU - Kerninon, Christophe
AU - Williams, Anna
AU - Krezel, Wojciech
AU - Kagechika, Hiroyuki
AU - Bauer, Julien
AU - Zhao, Chao
AU - Baron-Van Evercooren, Anne
AU - Chambon, Pierre
AU - Ffrench-Constant, Charles
AU - Franklin, Robin J. M.
N1 - © 2010 Macmillan Publishers Limited. All Rights Reserved.
PY - 2011/1
Y1 - 2011/1
N2 - The molecular basis of CNS myelin regeneration (remyelination) is poorly understood. We generated a comprehensive transcriptional profile of the separate stages of spontaneous remyelination that follow focal demyelination in the rat CNS and found that transcripts that encode the retinoid acid receptor RXR-gamma were differentially expressed during remyelination. Cells of the oligodendrocyte lineage expressed RXR-gamma in rat tissues that were undergoing remyelination and in active and remyelinated multiple sclerosis lesions. Knockdown of RXR-gamma by RNA interference or RXR-specific antagonists severely inhibited oligodendrocyte differentiation in culture. In mice that lacked RXR-gamma, adult oligodendrocyte precursor cells efficiently repopulated lesions after demyelination, but showed delayed differentiation into mature oligodendrocytes. Administration of the RXR agonist 9-cis-retinoic acid to demyelinated cerebellar slice cultures and to aged rats after demyelination caused an increase in remyelinated axons. Our results indicate that RXR-gamma is a positive regulator of endogenous oligodendrocyte precursor cell differentiation and remyelination and might be a pharmacological target for regenerative therapy in the CNS.
AB - The molecular basis of CNS myelin regeneration (remyelination) is poorly understood. We generated a comprehensive transcriptional profile of the separate stages of spontaneous remyelination that follow focal demyelination in the rat CNS and found that transcripts that encode the retinoid acid receptor RXR-gamma were differentially expressed during remyelination. Cells of the oligodendrocyte lineage expressed RXR-gamma in rat tissues that were undergoing remyelination and in active and remyelinated multiple sclerosis lesions. Knockdown of RXR-gamma by RNA interference or RXR-specific antagonists severely inhibited oligodendrocyte differentiation in culture. In mice that lacked RXR-gamma, adult oligodendrocyte precursor cells efficiently repopulated lesions after demyelination, but showed delayed differentiation into mature oligodendrocytes. Administration of the RXR agonist 9-cis-retinoic acid to demyelinated cerebellar slice cultures and to aged rats after demyelination caused an increase in remyelinated axons. Our results indicate that RXR-gamma is a positive regulator of endogenous oligodendrocyte precursor cell differentiation and remyelination and might be a pharmacological target for regenerative therapy in the CNS.
UR - http://www.scopus.com/inward/record.url?scp=78650632445&partnerID=8YFLogxK
U2 - 10.1038/nn.2702
DO - 10.1038/nn.2702
M3 - Article
C2 - 21131950
SN - 1097-6256
VL - 14
SP - 45
EP - 53
JO - Nature Neuroscience
JF - Nature Neuroscience
IS - 1
ER -