Comparative Biomedical Sciences Graduate Program, University of Wisconsin—Madison, Madison, Wisconsin, USA.
Mol Cell Biol. 2012 Jan;32(2):558-68. doi: 10.1128/MCB.06270-11. Epub 2011 Nov 7.
Schwann cell differentiation and subsequent myelination of the peripheral nervous system require the action of several transcription factors, including Sox10, which is vital at multiple stages of development. The transition from immature to myelinating Schwann cell is also regulated posttranscriptionally and depends upon Dicer-mediated processing of microRNAs (miRNAs). Although specific miRNA targets have begun to be identified, the mechanisms establishing the dynamic regulation of miRNA expression have not been elucidated. We performed expression profiling studies and identified 225 miRNAs differentially expressed during peripheral myelination. A subset of 9 miRNAs is positively regulated by Sox10, including miR-338 which has been implicated in oligodendrocyte maturation. In vivo chromatin immunoprecipitation (ChIP) of sciatic nerve cells revealed a Sox10 binding site upstream of an alternate promoter within the Aatk gene, which hosts miR-338. Sox10 occupied this site in spinal cord ChIP experiments, suggesting a similar regulatory mechanism in oligodendrocytes. Cancer profiling studies have identified clusters of miRNAs that regulate proliferation, termed "oncomirs." In Schwann cells, the expression of many of these proproliferative miRNAs was reduced in the absence of Sox10. Finally, Schwann cells with reduced Sox10 and oncomir expression have an increase in the CDK inhibitor p21 and a concomitant reduction in cell proliferation.
施万细胞分化和随后的周围神经系统髓鞘形成需要几种转录因子的作用，包括 Sox10，它在发育的多个阶段都是至关重要的。从未成熟的施万细胞向髓鞘形成细胞的转变也受到转录后调控，并依赖于 Dicer 介导的 microRNAs（miRNAs）的处理。尽管已经开始鉴定特定的 miRNA 靶标，但建立 miRNA 表达动态调控的机制尚未阐明。我们进行了表达谱研究，鉴定了在周围髓鞘形成过程中差异表达的 225 个 miRNAs。Sox10 正调控一组 9 个 miRNAs，包括已被牵连到少突胶质细胞成熟的 miR-338。体内坐骨神经细胞的染色质免疫沉淀（ChIP）揭示了 Aatk 基因内一个替代启动子上游的 Sox10 结合位点，该启动子包含 miR-338。Sox10 在脊髓 ChIP 实验中占据了这个位点，表明在少突胶质细胞中存在类似的调节机制。癌症基因谱研究已经确定了调节增殖的 miRNA 簇，称为“oncomirs”。在施万细胞中，许多这些促增殖 miRNAs 的表达在 Sox10 缺失的情况下减少。最后，Sox10 和 oncomir 表达减少的施万细胞中 CDK 抑制剂 p21 增加，同时细胞增殖减少。
