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Retinoid X receptor gamma signaling accelerates CNS remyelination

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.

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Figure 1: Differential expression of Rxrg in CNS remyelination transcriptome.
Figure 2: RXR-γ expression by oligodendrocyte lineage cells.
Figure 3: Expression of RXR-γ in multiple sclerosis lesions.
Figure 4: Loss of RXR-γ function impairs oligodendrocyte differentiation.
Figure 5: Rexinoids influence oligodendrocyte differentiation and myelination.
Figure 6: CNS remyelination is enhanced by 9 cis-retinoic acid.

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Acknowledgements

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.

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Authors and Affiliations

Authors

Contributions

J.K.H. performed in vivo experiments and laser capture microdissections. A.A.J. performed in vitro experiments. C.Z. contributed to in vivo experiments. A.W. performed ex vivo experiments. B.N.O., C.K. and A.B.-V.E. performed multiple sclerosis tissue analysis. H.K. generated RXR antagonists and agonists. W.K. and P.C. generated the RXR-γ mouse mutants. J.B. and J.K.H. performed bioinformatics. C.ff.-C. and R.J.M.F. equally oversaw the project.

Corresponding authors

Correspondence to Charles ffrench-Constant or Robin J M Franklin.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–7 and Supplementary Tables 5, 7 (PDF 1078 kb)

Supplementary Table 1

Total genes differentially expressed between 5, 14 and 28 days post CCP demyelination. (XLS 5299 kb)

Supplementary Table 2

Gene list used for IPA analysis. (XLS 96 kb)

Supplementary Table 3

Active signaling networks found between 5 and 14 dpl. (XLS 66 kb)

Supplementary Table 4

Total genes differentially expressed between 5 and 14 dpl (P < 0.05) used for volcano plot. (XLS 714 kb)

Supplementary Table 6

IPA identified RXR associated pathways from the remyelination transcriptome. (XLS 199 kb)

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Huang, J., Jarjour, A., Nait Oumesmar, B. et al. Retinoid X receptor gamma signaling accelerates CNS remyelination. Nat Neurosci 14, 45–53 (2011). https://doi.org/10.1038/nn.2702

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