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 - Evercooren, Anne Baron Van
AU - Chambon, Pierre
AU - Ffrench-Constant, Charles
AU - Franklin, Robin J.M.
N1 - Funding Information:
We thank D. Seilhean (Service d’Anatomopathologie Neurologique, G-H Pitié-Salpêtrière, Paris) for classification of multiple sclerosis lesions, the French Brain Bank GIE NeuroCEB (Hôpital Pitié-Salpêtrière, Paris, France) and the United Kingdom Multiple Sclerosis Society Brain Bank (R. Reynolds, Imperial College, London) for multiple sclerosis tissue. All tissues were collected with the approval of the French and London Multicentre Research Ethics committees. Animal procedures were performed under a UK Home Office Project License. This work was supported by grants from the United Kingdom Multiple Sclerosis Society (R.J.M.F., C.ff.-C.), the Wellcome Trust (C.ff.-C.), the French Multiple Sclerosis foundation ARSEP (B.N.O.), the Biotechnology and Biological Sciences Research Council of the United Kingdom (C.ff.-C., J.B.), National Multiple Sclerosis Society (C.ff.-C., R.J.M.F., A.B.-V.E., B.N.O.), AP-HP Hôpital Pitié-Salpêtrière, Service d’Anatomopathologie Neurologique (B.N.O.) et des Maladies du Système Nerveux (A.B.-V.E.). A.W. holds a Wellcome Trust Intermediate Fellowship. A.A.J. holds a Fellowship from Multiple Sclerosis Society of Canada.
PY - 2011/12/5
Y1 - 2011/12/5
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-γ were differentially expressed during remyelination. Cells of the oligodendrocyte lineage expressed RXR-γ in rat tissues that were undergoing remyelination and in active and remyelinated multiple sclerosis lesions. Knockdown of RXR-γ by RNA interference or RXR-specific antagonists severely inhibited oligodendrocyte differentiation in culture. In mice that lacked RXR-γ, 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-γ 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-γ were differentially expressed during remyelination. Cells of the oligodendrocyte lineage expressed RXR-γ in rat tissues that were undergoing remyelination and in active and remyelinated multiple sclerosis lesions. Knockdown of RXR-γ by RNA interference or RXR-specific antagonists severely inhibited oligodendrocyte differentiation in culture. In mice that lacked RXR-γ, 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-γ 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
AN - SCOPUS:78650632445
VL - 14
SP - 45
EP - 55
JO - Nature Neuroscience
JF - Nature Neuroscience
SN - 1097-6256
IS - 1
ER -