Fine-tuning the onset of myogenesis by homeobox proteins that interact with the Myf5 limb enhancer.
Fine-tuning the onset of myogenesis by homeobox proteins that interact with the Myf5 limb enhancer.
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DOI：
10.1242/bio.014068
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发表时间：
2015-11-04
期刊：
影响因子：
2.4
通讯作者：
Buckingham M
中科院分区：
文献类型：
--
作者：
Daubas P;Duval N;Bajard L;Langa Vives F;Robert B;Mankoo BS;Buckingham M
脊椎动物骨骼肌的发生是在发育过程中骨骼肌形成的不同部位，通过激活成肌调节基因的特定控制元件而启动的。在小鼠胚胎中，Myf 5是第一个表达的肌生成决定基因，其时空调控需要多个增强子序列，在Mrf 4-Myf 5基因座上游延伸超过120 kb。 位于Myf 5的−57/−58 kb处的增强子负责其在肌原细胞中的激活，这些细胞来自体节的轴下结构域，将形成肢体肌肉。 Pax 3和Six 1/4转录因子是该增强子的重要激活因子，作用于145 bp的核心元件。将形成肢体的未来肌肉块的肌源性祖细胞在它们从下轴皮肌节分层并迁移到前肢芽中时表达Myf 5激活所必需的因子，然而它们不激活Myf 5和肌源性程序，直到它们填充了预期的肌肉块。我们发现，Msx 1和Meox 2同源结构域的转录因子结合在体外和体内的特定位点的145 bp的元素，并参与微调激活的Myf 5在前肢。Msx 1，当Pax和Six位点之间结合时，阻止这些关键激活剂的结合，从而抑制Myf 5的转录和随后的过早肌源性分化。Meox 2是Myf 5在肌生成开始时通过直接结合该序列中的其他同源结构域位点而激活所必需的。因此，这些同源结构域因子，除了Pax 3和Six 1/4，微调进入前肢发育的早期阶段的肌发生的祖细胞。总结：同源结构域因子Msx 1和Meox 2，除了Pax 3和Six 1/4，通过调节肢体增强子基因Myf 5，在前肢发育的早期阶段微调祖细胞进入肌发生。
Skeletal myogenesis in vertebrates is initiated at different sites of skeletal muscle formation during development, by activation of specific control elements of the myogenic regulatory genes. In the mouse embryo, Myf5 is the first myogenic determination gene to be expressed and its spatiotemporal regulation requires multiple enhancer sequences, extending over 120 kb upstream of the Mrf4-Myf5 locus. An enhancer, located at −57/−58 kb from Myf5, is responsible for its activation in myogenic cells derived from the hypaxial domain of the somite, that will form limb muscles. Pax3 and Six1/4 transcription factors are essential activators of this enhancer, acting on a 145-bp core element. Myogenic progenitor cells that will form the future muscle masses of the limbs express the factors necessary for Myf5 activation when they delaminate from the hypaxial dermomyotome and migrate into the forelimb bud, however they do not activate Myf5 and the myogenic programme until they have populated the prospective muscle masses. We show that Msx1 and Meox2 homeodomain-containing transcription factors bind in vitro and in vivo to specific sites in the 145-bp element, and are implicated in fine-tuning activation of Myf5 in the forelimb. Msx1, when bound between Pax and Six sites, prevents the binding of these key activators, thus inhibiting transcription of Myf5 and consequent premature myogenic differentiation. Meox2 is required for Myf5 activation at the onset of myogenesis via direct binding to other homeodomain sites in this sequence. Thus, these homeodomain factors, acting in addition to Pax3 and Six1/4, fine-tune the entry of progenitor cells into myogenesis at early stages of forelimb development. Summary: Homeodomain factors Msx1 and Meox2, acting in addition to Pax3 and Six1/4, fine-tune the entry of progenitor cells into myogenesis at early stages of forelimb development via modulation of limb enhancer gene Myf5.