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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Six proteins regulate the activation of Myf5 expression in embryonic mouse limbs
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Six proteins regulate the activation of Myf5 expression in embryonic mouse limbs

机译：六种蛋白质调节胚胎小鼠四肢Myf5表达的激活

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摘要

Myf5, a member of the myogenic regulatory factor family, plays a major role in determining myogenic cell fate at the onset of skeletal muscle formation in the embryo. Spatiotemporal control of its expression during development requires multiple enhancer elements spread over > 100 kb at the Myf5 locus. Transcription in embryonic limbs is regulated by a 145-bp element located at -57.5 kb from the Myf5 gene. In the present study we show that Myf5 expression is severely impaired in the limb buds of Six1~(-/-) and Six1~(-/-)Six4~(-/+) mouse mutants despite the presence of myogenic progenitor cells. The 145-bp regulatory element contains a sequence that binds Six1 and Six4 in electromobility shift assays in vitro and in chromatin immunoprecipitation assays with embryonic extracts. We further show that Six1 is able to transactivate a reporter gene under the control of this sequence. In vivo functionality of the Six binding site is demonstrated by transgenic analysis. Mutation of this site impairs reporter gene expression in the limbs and in mature somites where the 145-bp regulatory element is also active. Six1/4 therefore regulate Myf5 transcription, together with Pax3, which was previously shown to be required for the activity of the 145-bp element. Six homeoproteins, which also directly regulate the myogenic differentiation gene Myogenin and lie genetically upstream of Pax3. thus control hypaxial myogenesis at multiple levels.
机译：Myf5是肌源性调节因子家族的成员，在确定胚胎中骨骼肌形成时的肌源性细胞命运中起着重要作用。在发育过程中对其表达的时空控制要求在Myf5基因座上分布超过100 kb的多个增强子元件。胚胎肢体中的转录受Myf5基因的-57.5 kb处145 bp元件的调控。在本研究中，我们表明尽管存在成肌祖细胞，但在Six1〜（-/-）和Six1〜（-/-）Six4〜（-/ +）小鼠突变体的肢芽中，Myf5表达受到严重损害。 145 bp的调控元件包含一个序列，该序列在体外电迁移率测定中和在用胚胎提取物进行染色质免疫沉淀测定中结合Six1和Six4。我们进一步表明，Six1能够在此序列的控制下转导报告基因。通过转基因分析证明了六个结合位点的体内功能。此位点的突变会损害肢体和145 bp调节元件也活跃的成熟子节中的报告基因表达。因此，Six1 / 4与Pax3一起调节Myf5转录，Pax3先前被证明是145-bp元件活性所必需的。六种同源蛋白，它们也直接调节成肌分化基因Myogenin，并且在基因上位于Pax3的上游。因此可以在多个层面上控制下轴肌发生。

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