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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Aged
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Alitretinoin
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Animals
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Benzoates / pharmacology
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Biphenyl Compounds / pharmacology
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Cell Differentiation / physiology
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Cell Lineage / genetics
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Cells, Cultured
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Central Nervous System / metabolism*
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Central Nervous System / pathology
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Cerebellum / drug effects
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Cerebellum / metabolism
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Demyelinating Diseases / chemically induced
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Demyelinating Diseases / metabolism
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Female
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Gene Expression Profiling
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Humans
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Male
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Mice
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Mice, Knockout
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Middle Aged
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Multiple Sclerosis / metabolism
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Multiple Sclerosis / pathology
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Myelin Sheath / drug effects
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Myelin Sheath / genetics
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Myelin Sheath / metabolism*
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Nerve Regeneration / genetics
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Nerve Regeneration / physiology*
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Neurotoxins
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Oligodendroglia / cytology
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Oligodendroglia / metabolism
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Oligodendroglia / physiology
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RNA Interference
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Rats
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Rats, Sprague-Dawley
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Receptors, Retinoic Acid / agonists
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Receptors, Retinoic Acid / antagonists & inhibitors
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Receptors, Retinoic Acid / genetics
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Receptors, Retinoic Acid / physiology*
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Retinoic Acid Receptor gamma
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Stem Cells / cytology
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Stem Cells / metabolism
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Stem Cells / physiology
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Tretinoin / pharmacology
Substances
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Benzoates
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Biphenyl Compounds
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Neurotoxins
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Receptors, Retinoic Acid
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diazepinylbenzoic acid
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Alitretinoin
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Tretinoin