MRC Centre for Stem Cell Biology and Regenerative Medicine and Department of Veterinary Medicine, University of Cambridge, Cambridge, UK.
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.
Nat Neurosci. 2011 Jan;14(1):45-53. doi: 10.1038/nn.2702. Epub 2010 Dec 5.
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.
中枢神经系统髓鞘再生（再髓鞘化）的分子基础知之甚少。我们生成了一个大鼠中枢神经系统局灶性脱髓鞘后自发再髓鞘化各阶段的综合转录谱，发现编码视黄酸受体 RXR-γ的转录本在再髓鞘化过程中存在差异表达。在经历再髓鞘化的大鼠组织以及活动期和再髓鞘化多发性硬化病变中，寡突胶质细胞谱系的细胞表达 RXR-γ。用 RNA 干扰或 RXR 特异性拮抗剂敲低 RXR-γ，严重抑制了培养中的少突胶质细胞分化。在缺乏 RXR-γ的小鼠中，成年少突胶质前体细胞在脱髓鞘后能有效地重新填充病变，但向成熟少突胶质细胞的分化延迟。在脱髓鞘小脑切片培养物和脱髓鞘后老龄大鼠中给予 RXR 激动剂 9-顺式视黄酸，可导致再髓鞘化轴突增加。我们的结果表明，RXR-γ 是内源性少突胶质前体细胞分化和再髓鞘化的正调节剂，可能是中枢神经系统再生治疗的药理学靶点。
