miR-133-mediated regulation of the Hedgehog pathway orchestrates embryo myogenesis.
miR-133-mediated regulation of the Hedgehog pathway orchestrates embryo myogenesis.
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DOI：
10.1242/dev.159657
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发表时间：
2018-06-11
期刊：
影响因子：
--
通讯作者：
Münsterberg A
中科院分区：
文献类型：
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作者：
Mok GF;Lozano-Velasco E;Maniou E;Viaut C;Moxon S;Wheeler G;Münsterberg A
骨骼肌发生是研究胚胎发育中细胞命运决定精细调控的分子机制的一个范例。进化上保守的miR-133家族microRNA在肌源性谱系中表达，但其作用方式仍不完全清楚。在这里，我们进行了全基因组差异转录组学的miR-133敲低（KD）胚胎体节，脊椎动物骨骼肌的来源。在鸡胚中进行的这些分析揭示了Sonic hedgehog（Shh）通路组分的广泛下调：补丁受体、Hedgehog相互作用蛋白和转录激活因子Gli 1。相反，Gli 3，一种转录抑制因子，被去抑制并被证实为直接的miR-133靶标。在表型上，miR-133 KD通过破坏增殖、细胞外基质沉积和上皮形成来损害肌节形成和生长。总之，这些观察结果表明，miR-133介导的Gli 3沉默对胚胎肌发生至关重要。与这一想法一致，我们发现通过purmorphamine激活Shh信号传导，或通过反义吗啉代激活Gli 3的KD，拯救了miR-133 KD表型。因此，我们确定了一个新的Shh/生肌调节因子/miR-133/Gli 3轴，连接上皮形态发生与生肌命运规范。总结：在这里，使用鸡胚，我们表明，转录后沉默的Gli 3阻遏物的miR-133是需要稳定地建立早期体节的生肌程序。
Skeletal myogenesis serves as a paradigm to investigate the molecular mechanisms underlying exquisitely regulated cell fate decisions in developing embryos. The evolutionarily conserved miR-133 family of microRNAs is expressed in the myogenic lineage, but how it acts remains incompletely understood. Here, we performed genome-wide differential transcriptomics of miR-133 knockdown (KD) embryonic somites, the source of vertebrate skeletal muscle. These analyses, performed in chick embryos, revealed extensive downregulation of Sonic hedgehog (Shh) pathway components: patched receptors, Hedgehog interacting protein and the transcriptional activator Gli1. By contrast, Gli3, a transcriptional repressor, was de-repressed and confirmed as a direct miR-133 target. Phenotypically, miR-133 KD impaired myotome formation and growth by disrupting proliferation, extracellular matrix deposition and epithelialization. Together, these observations suggest that miR-133-mediated Gli3 silencing is crucial for embryonic myogenesis. Consistent with this idea, we found that activation of Shh signalling by either purmorphamine, or KD of Gli3 by antisense morpholino, rescued the miR-133 KD phenotype. Thus, we identify a novel Shh/myogenic regulatory factor/miR-133/Gli3 axis that connects epithelial morphogenesis with myogenic fate specification. Summary: Here, using chick embryos, we showed that post-transcriptional silencing of the Gli3 repressor by miR-133 is required to stably establish the myogenic programme in early somites.
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