Journal
NATURE NEUROSCIENCE
Volume 14, Issue 1, Pages 45-U68Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nn.2702
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Funding
- United Kingdom Multiple Sclerosis Society
- Wellcome Trust
- French Multiple Sclerosis foundation ARSEP
- Biotechnology and Biological Sciences Research Council of the United Kingdom
- National Multiple Sclerosis Society
- AP-HP Hopital Pitie-Salpetriere, Service d'Anatomopathologie Neurologique et des Maladies du Systeme Nerveux
- Multiple Sclerosis Society of Canada
- Medical Research Council [G0700711B] Funding Source: researchfish
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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.
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