Retinoid X receptor gamma signaling accelerates CNS remyelination.
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.
MRC Centre for Stem Cell Biology and Regenerative Medicine and Department of Veterinary Medicine, University of Cambridge, Cambridge, UK.
Jeffrey K
JK
Huang
MRC Centre for Regenerative Medicine and Multiple Sclerosis Society/University of Edinburgh Centre for Translational Research, Centre for Inflammation Research, The Queen's Medical Research Institute, Edinburgh, UK.
Andrew A
AA
Jarjour
Centre de Recherche de l'Institut du Cerveau et de la Moelle Epinière, Inserm U.975; Université Pierre et Marie Curie-Paris 6 UMR-S975; Cnrs UMR 7225; and AP-HP Groupe Hospitalier Pitié-Salpêtrière, Fédération de Neurologie, Paris cedex 13, France.
Brahim
B
Nait Oumesmar
Centre de Recherche de l'Institut du Cerveau et de la Moelle Epinière, Inserm U.975; Université Pierre et Marie Curie-Paris 6 UMR-S975; Cnrs UMR 7225; and AP-HP Groupe Hospitalier Pitié-Salpêtrière, Fédération de Neurologie, Paris cedex 13, France.
Christophe
C
Kerninon
MRC Centre for Regenerative Medicine and Multiple Sclerosis Society/University of Edinburgh Centre for Translational Research, Centre for Inflammation Research, The Queen's Medical Research Institute, Edinburgh, UK.
Anna
A
Williams
Institut de Génétique et de Biologie Moléculaire et Cellulaire, Department of Cell Biology and Development, Illkirch, France.
Wojciech
W
Krezel
Graduate School of Biomedical Science, Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, Chiyoda-ku, Tokyo, Japan.
Hiroyuki
H
Kagechika
Department of Pathology, University of Cambridge, Cambridge, UK.
Julien
J
Bauer
MRC Centre for Stem Cell Biology and Regenerative Medicine and Department of Veterinary Medicine, University of Cambridge, Cambridge, UK.
Chao
C
Zhao
Centre de Recherche de l'Institut du Cerveau et de la Moelle Epinière, Inserm U.975; Université Pierre et Marie Curie-Paris 6 UMR-S975; Cnrs UMR 7225; and AP-HP Groupe Hospitalier Pitié-Salpêtrière, Fédération de Neurologie, Paris cedex 13, France.
Anne
A
Baron-Van Evercooren
Institut de Génétique et de Biologie Moléculaire et Cellulaire, Department of Cell Biology and Development, Illkirch, France.
Pierre
P
Chambon
MRC Centre for Regenerative Medicine and Multiple Sclerosis Society/University of Edinburgh Centre for Translational Research, Centre for Inflammation Research, The Queen's Medical Research Institute, Edinburgh, UK.
Charles
C
Ffrench-Constant
MRC Centre for Stem Cell Biology and Regenerative Medicine and Department of Veterinary Medicine, University of Cambridge, Cambridge, UK.
Robin J M
RJM
Franklin
D000368:Aged; D000077556:Alitretinoin; D000818:Animals; D001565:Benzoates / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000494:pharmacology; D002454:Cell Differentiation / Q000502:physiology; D019070:Cell Lineage / Q000235:genetics; D002478:Cells, Cultured; D002490:Central Nervous System / Q000378:metabolism* / Q000473:pathology; D002531:Cerebellum / Q000187:drug effects / Q000378:metabolism; D003711:Demyelinating Diseases / Q000139:chemically induced / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000378:metabolism / Q000473:pathology; D009186:Myelin Sheath / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D009416:Nerve Regeneration / Q000235:genetics / Q000502:physiology*; D009498:Neurotoxins; D009836:Oligodendroglia / Q000166:cytology / Q000378:metabolism / Q000502:physiology; D034622:RNA Interference; D051381:Rats; D017207:Rats, Sprague-Dawley; D018168:Receptors, Retinoic Acid / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism / Q000502:physiology; D014212:Tretinoin / Q000494:pharmacology; D000097768:Retinoic Acid Receptor gamma
D000077556:Alitretinoin; D001565:Benzoates; D001713:Biphenyl Compounds; D009498:Neurotoxins; D018168:Receptors, Retinoic Acid; D014212:Tretinoin; D000097768:Retinoic Acid Receptor gamma; C438269:diazepinylbenzoic acid