Retinoid X receptor gamma signaling accelerates CNS remyelination

The molecular basis of CNS myelin regeneration (remyelination) is poorly understood. Here we generate a comprehensive transcriptional profile of the separate stages of spontaneous remyelination following focal demyelination in the rat CNS. White matter tracts in the rat caudal cerebellar peduncles were focally demyelinated using 0.1% ethidium bromide, the lesions were isolated using laser capture microdissection at 5, 14 and 28 days postlesion, followed by RNA extraction and Illumina beadarray analysis of differentially expressed transcripts. We found transcripts encoding retinoid acid receptor RXR-gamma is highly differentially expressed during remyelination, and that oligodendrocyte lineage cells express RXR-gamma in rat tissues undergoing remyelination and in active and remyelinated MS lesions. RXR-gamma knockdown by RNA interference or RXR-specific antagonists severely inhibit oligodendrocyte differentiation in culture. In RXR-gamma deficient mice, adult oligodendrocyte precursor cells efficiently repopulate lesions following demyelination, but display delayed differentiation into mature oligodendrocytes. Administration of the RXR agonist 9-cis-retinoic acid to demyelinated cerebellar slice cultures and to aged rats following demyelination results in more remyelinated axons. RXR-gamma is therefore a positive regulator of endogenous oligodendrocyte precursor cell differentiation and remyelination, and may be a pharmacological target for CNS regenerative therapy.中枢神经系统（Central Nervous System, CNS）髓鞘再生（remyelination）的分子基础迄今仍未被充分阐明。本研究针对大鼠中枢神经系统局灶性脱髓鞘后自发再髓鞘化的不同阶段，构建了全面的转录组图谱（transcriptional profile）。研究人员使用0.1%溴化乙锭（ethidium bromide）对大鼠尾侧小脑脚的白质束进行局灶性脱髓鞘处理，并在损伤后5、14及28天通过激光捕获显微切割（laser capture microdissection）分离损伤区域，随后进行RNA提取，以及对差异表达转录本（differentially expressed transcripts）进行Illumina微珠芯片（Illumina beadarray）分析。我们发现，编码维甲酸受体RXR-γ（retinoid acid receptor RXR-γ）的转录本在再髓鞘化过程中呈现显著差异表达，且在发生再髓鞘化的大鼠组织、活动性多发性硬化（Multiple Sclerosis, MS）病灶及再髓鞘化病灶中，少突胶质细胞（oligodendrocyte）谱系细胞均表达RXR-γ。通过RNA干扰（RNA interference, RNAi）或RXR特异性拮抗剂敲低RXR-γ的表达，会显著抑制体外培养的少突胶质细胞的分化。在RXR-γ缺陷型小鼠中，成年少突胶质前体细胞（oligodendrocyte precursor cell）在脱髓鞘后可有效浸润损伤区域，但向成熟少突胶质细胞的分化过程出现延迟。向脱髓鞘的小脑脑片培养物及脱髓鞘后的老年大鼠施加RXR激动剂9-顺式维甲酸（9-cis-retinoic acid），可使其形成更多再髓鞘化轴突。因此，RXR-γ是内源性少突胶质前体细胞分化及再髓鞘化的正向调控因子，有望成为中枢神经系统再生治疗的药理学靶点。