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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >MicroRNA regulation of the paired-box transcription factor Pax3 confers robustness to developmental timing of myogenesis
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MicroRNA regulation of the paired-box transcription factor Pax3 confers robustness to developmental timing of myogenesis

机译：配对盒转录因子Pax3的MicroRNA调控赋予了成肌发育时机鲁棒性

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摘要

Commitment of progenitors in the dermomyotome to myoblast fate is the first step in establishing the body musculature. Pax3 is a crucial transcription factor, important for skeletal muscle development and expressed in myogenic progenitors in the dermomyotome of developing somites and in migratory muscle progenitors that populate the limb buds. Down-regulation of Pax3 is essential to ignite the myogenic program, including up-regulation of myogenic regulators, Myf-5 and MyoD. MicroRNAs (miRNAs) confer robustness to developmental timing by posttranscriptional repression of genetic programs that are related to previous developmental stages or to alternative cell fates. Here we demonstrate that the muscle-specific miRNAs miR-1 and miR-206 directly target Pax3. Antagomir-mediated inhibition of miR-1/miR-206 led to delayed myogenic differentiation in developing somites, as shown by transient loss of myogenin expression. This correlated with increased Pax3 and was phenocopied using Pax3-specif ic target protectors. Loss of myogenin after antagomir injection was rescued by Pax3 knockdown using a splice morpholino, suggesting that miR-1/miR-206 control somite myogenesis primarily through interactions with Pax3. Our studies reveal an important role for miR-1/miR-206 in providing precision to the timing of somite myogenesis. We propose that posttranscriptional control of Pax3 downstream of miR-1/miR-2u6 is required to stabilize myoblast commitment and subsequent differentiation. Given that mutually exclusive expression of miRNAs and their targets is a prevailing theme in development, our findings suggest that miRNA may provide a general mechanism for the unequivocal commitment underlying stem cell differentiation.
机译：皮肌球蛋白的祖细胞致力于成肌细胞的命运是建立身体肌肉系统的第一步。 Pax3是至关重要的转录因子，对骨骼肌的发育很重要，并在发育中的体节的皮肤肌球体的成肌祖细胞中以及在四肢芽中生长的迁徙性肌肉祖细胞中表达。 Pax3的下调对于点燃肌生成程序至关重要，包括肌生成的调节剂Myf-5和MyoD的上调。 MicroRNA（miRNA）通过转录后抑制基因程序来赋予发育时机鲁棒性，该遗传程序与先前的发育阶段或与其他细胞命运有关。在这里，我们证明了肌肉特异性miRNA miR-1和miR-206直接靶向Pax3。 Antagomir介导的对miR-1 / miR-206的抑制作用导致发育中的卵节中的肌原性分化延迟，如肌生成素表达的瞬时丧失所证明。这与增加的Pax3相关，并使用Pax3特异的靶标保护剂进行了表型复制。使用剪接吗啉代物通过Pax3敲低挽救了注射antagomir后肌原蛋白的损失，这表明miR-1 / miR-206主要通过与Pax3的相互作用来控制体节肌的发生。我们的研究揭示了miR-1 / miR-206在提供精确的体节肌发生时间方面的重要作用。我们建议需要miR-1 / miR-2u6下游Pax3的转录后控制，以稳定成肌细胞的承诺和随后的分化。鉴于miRNA及其靶标的互斥表达是开发中的主要主题，我们的发现表明miRNA可能为干细胞分化的明确承诺提供一般机制。

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