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Nat Neurosci. 2011 Jan;14(1):45-53. doi: 10.1038/nn.2702. Epub 2010 Dec 5.

Retinoid X receptor gamma signaling accelerates CNS remyelination.

Author information

1
MRC Centre for Stem Cell Biology and Regenerative Medicine and Department of Veterinary Medicine, University of Cambridge, Cambridge, UK.
2
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.
3
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.
4
Institut de Génétique et de Biologie Moléculaire et Cellulaire, Department of Cell Biology and Development, Illkirch, France.
5
Graduate School of Biomedical Science, Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, Chiyoda-ku, Tokyo, Japan.
6
Department of Pathology, University of Cambridge, Cambridge, UK.
#
Contributed equally

Abstract

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.

Comment in

PMID:
21131950
PMCID:
PMC4013508
DOI:
10.1038/nn.2702
[Indexed for MEDLINE]
Free PMC Article

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