Microrna-221 and microrna-222 modulate differentiation and maturation of skeletal muscle cells.
Microrna-221 and microrna-222 modulate differentiation and maturation of skeletal muscle cells.
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DOI：
10.1371/journal.pone.0007607
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发表时间：
2009-10-27
期刊：
影响因子：
3.7
通讯作者：
Falcone G
中科院分区：
文献类型：
--
作者：
Cardinali B;Castellani L;Fasanaro P;Basso A;Alemà S;Martelli F;Falcone G
微小核糖核酸（miRNAs）是一类小型非编码核糖核酸，最近已成为基因表达的重要调节因子。它们通过翻译抑制和靶向信使核糖核酸降解在转录后对基因表达进行负调控。已表明miRNAs在肌肉发育以及肌肉细胞增殖和分化的调控中发挥关键作用。
通过比较增殖的成肌细胞与分化的肌管的miRNA表达谱，鉴定出了一些之前未涉及肌源性分化调控的受调控的miRNAs。其中，miR - 221和miR - 222在原代和已建立的肌源细胞分化时均强烈下调。相反，在经历Src酪氨酸激酶激活的有丝分裂后终末分化的肌管中，miR - 221和miR - 222的表达得以恢复。通过使用特异性抑制剂，我们提供的证据表明miR - 221和miR - 222的表达受Ras - MAPK通路的控制。在成肌细胞和肌管中，细胞周期抑制剂p27的水平与miR - 221和miR - 222的表达呈负相关，并且我们确实表明p27信使核糖核酸是这些miRNAs在肌源细胞中的直接靶标。在正在分化的成肌细胞中异位表达miR - 221和miR - 222会导致细胞周期退出延迟和肌细胞生成素表达延迟，进而抑制肌节蛋白的积累。当miR - 221和miR - 222在正在成熟的肌管中表达时，观察到肌原纤维组织发生了显著改变。
已发现miR - 221和miR - 222在肌生成过程中受到调控，并在从成肌细胞到肌细胞的进展以及完全分化表型的实现中都发挥作用。鉴定调节肌肉基因表达的miRNAs对于理解控制骨骼肌分化和维持的回路至关重要。
MicroRNAs (miRNAs) are a class of small non-coding RNAs that have recently emerged as important regulators of gene expression. They negatively regulate gene expression post-transcriptionally by translational repression and target mRNA degradation. miRNAs have been shown to play crucial roles in muscle development and in regulation of muscle cell proliferation and differentiation. By comparing miRNA expression profiling of proliferating myoblasts versus differentiated myotubes, a number of modulated miRNAs, not previously implicated in regulation of myogenic differentiation, were identified. Among these, miR-221 and miR-222 were strongly down-regulated upon differentiation of both primary and established myogenic cells. Conversely, miR-221 and miR-222 expression was restored in post-mitotic, terminally differentiated myotubes subjected to Src tyrosine kinase activation. By the use of specific inhibitors we provide evidence that expression of miR-221 and miR-222 is under the control of the Ras-MAPK pathway. Both in myoblasts and in myotubes, levels of the cell cycle inhibitor p27 inversely correlated with miR-221 and miR-222 expression, and indeed we show that p27 mRNA is a direct target of these miRNAs in myogenic cells. Ectopic expression of miR-221 and miR-222 in myoblasts undergoing differentiation induced a delay in withdrawal from the cell cycle and in myogenin expression, followed by inhibition of sarcomeric protein accumulation. When miR-221 and miR-222 were expressed in myotubes undergoing maturation, a profound alteration of myofibrillar organization was observed. miR-221 and miR-222 have been found to be modulated during myogenesis and to play a role both in the progression from myoblasts to myocytes and in the achievement of the fully differentiated phenotype. Identification of miRNAs modulating muscle gene expression is crucial for the understanding of the circuits controlling skeletal muscle differentiation and maintenance.