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Developmental Regulation of MicroRNA Expression in Schwann Cells

机译：雪旺细胞中MicroRNA表达的发育调控

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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.
机译：雪旺氏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，Sox10在发育的多个阶段至关重要。从未成熟的到有髓的雪旺氏细胞的过渡在转录后也受到调控，并取决于 Dicer 介导的微小RNA（miRNA）的加工。尽管已经开始确定特定的miRNA靶标，但尚未阐明建立miRNA表达动态调节的机制。我们进行了表达谱研究，并鉴定了在外周髓鞘形成过程中差异表达的225个miRNA。 9个miRNA的子集受到Sox10的正调控，其中包括与少突胶质细胞成熟有关的miR-338。坐骨神经细胞的体内染色质免疫沉淀（ChIP）结果显示， Aatk 基因内另一个启动子上游有一个Sox10结合位点，该基因是miR-338宿主。 Sox10在脊髓ChIP实验中占据了该位点，表明少突胶质细胞具有类似的调节机制。癌症分析研究已经确定了调控增殖的miRNA簇，被称为“ oncomirs”。在雪旺细胞中，在没有Sox10的情况下，许多这些增生性miRNA的表达降低了。最后，具有减少的Sox10和癌基因表达的雪旺细胞具有CDK抑制剂p21的增加和细胞增殖的同时减少。

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