Journal Article

Retinoid X receptor gamma signaling accelerates CNS remyelination

Nait Oumesmar, Brahim, Evercooren, Anne Baron-Van, Franklin, Robin J M, Krezel, Wojciech, Huang, Jeffrey K, Chambon, Pierre, Kagechika, Hiroyuki, ffrench-Constant, Charles, Jarjour, Andrew A, Bauer, Julien, Kerninon, Christophe, Williams, Anna, Zhao, Chao

2011

Overview

The authors report a transcriptional profile of the discrete stages of spontaneous remyelination following toxin-induced focal demyelination in rats. They find an enrichment of retinoid X receptor (RXR) signaling pathways over the course of remyelination and show that RXR activation stimulates oligodendrocyte differentiation to enhance 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.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/136/142 / 631/378/1687 / 631/378/2571/219 / 692/699/375 / Aged / Alitretinoin / Animal Genetics and Genomics / Animals / Behavioral Sciences / Benzoates - pharmacology / Biochemistry, Molecular Biology / Biological Techniques / Biomedical and Life Sciences / Biomedicine / Biphenyl Compounds - pharmacology / Cell Differentiation - physiology / Cell Lineage - genetics / Cell receptors / Cells, Cultured / Central nervous system / Central Nervous System - metabolism / Central Nervous System - pathology / Cerebellum - drug effects / Cerebellum - metabolism / Demyelinating Diseases - chemically induced / Demyelinating Diseases - metabolism / Female / Gene Expression Profiling / Humans / Life Sciences / Male / Mice / Mice, Knockout / Middle Aged / Multiple sclerosis / Multiple Sclerosis - metabolism / Multiple Sclerosis - pathology / Myelin Sheath - drug effects / Myelin Sheath - genetics / Myelin Sheath - metabolism / Myelination / Nerve Regeneration - genetics / Nerve Regeneration - physiology / Neurobiology / Neurosciences / Neurotoxins / Oligodendroglia - cytology / Oligodendroglia - metabolism / Oligodendroglia - physiology / Physiological aspects / Rats / Rats, Sprague-Dawley / Receptors, Retinoic Acid - agonists / Receptors, Retinoic Acid - antagonists & inhibitors / Receptors, Retinoic Acid - genetics / Receptors, Retinoic Acid - physiology / Regenerative medicine / Retinoic Acid Receptor gamma / RNA Interference / Stem Cells - cytology / Stem Cells - metabolism / Stem Cells - physiology / Tretinoin - pharmacology