The homeobox gene Arx is a novel positive regulator of embryonic myogenesis
The homeobox gene Arx is a novel positive regulator of embryonic myogenesis
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DOI：
10.1038/sj.cdd.4402230
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发表时间：
2008-01-01
影响因子：
12.4
通讯作者：
Cossu, G.
中科院分区：
文献类型：
--
作者：
Biressi, S.;Messina, G.;Cossu, G.
骨骼肌纤维以重叠但不同的阶段形成，这取决于时间上不同的生肌细胞谱系的生成。在初级肌生成过程中（小鼠中的 E10.5-E12.5），胚胎成肌细胞同型融合以产生初级纤维，而在后期发育过程中（E14.5-E17.5），胎儿成肌细胞分化为次级纤维。这些肌源波是如何调节的仍然很大程度上未知。由于缺乏区分胚胎和胎儿成肌细胞群的标记，研究受到阻碍。我们在这里表明，同源框基因 Arx 在分化的胚胎肌肉中强烈表达，位于生肌基本螺旋-环-螺旋 (bHLH) 基因的下游。其表达在发育过程中逐渐减少。当 Arx 在 C2C12 生肌细胞系中过度表达时，Arx 会增强分化。因此，当与 CH310T1/2 中的 MyoD 和 Mef2C 共表达时，它会刺激肌细胞生成素启动子和多聚化 E-box 的转录活性。此外，Arx 与 Mef2C 发生免疫共沉淀，表明它参与了胚胎肌肉中的转录调控网络。最后，从 Arx 缺陷胚胎中分离的胚胎成肌细胞显示出体内分化延迟以及体外克隆形成能力增强。我们在此提出，Arx 通过与 Mef2C 和 MyoD 协同作用并与 Myogenin 建立激活环，充当胚胎肌发生的新型正调节因子。
Skeletal muscle fibers form in overlapping, but distinct phases that depend on the generation of temporally different lineages of myogenic cells. During primary myogenesis (E10.5-E12.5 in the mouse), embryonic myoblasts fuse homotypically to generate primary fibers, whereas during later development (E14.5-E17.5), fetal myoblasts differentiate into secondary fibers. How these myogenic waves are regulated remains largely unknown. Studies have been hampered by the lack of markers which would distinguish embryonic from fetal myoblast populations. We show here that the homeobox gene Arx is strongly expressed in differentiating embryonic muscle, downstream of myogenic basic helix-loop-helix (bHLH) genes. Its expression progressively decreases during development. When overexpressed in the C2C12 myogenic cell line, Arx enhances differentiation. Accordingly, it stimulates the transcriptional activity from the Myogenin promoter and from multimerized E-boxes when co-expressed with MyoD and Mef2C in CH310T1/2. Furthermore, Arx co-immunoprecipitates with Mef2C, suggesting that it participates in the transcriptional regulatory network acting in embryonic muscle. Finally, embryonic myoblasts isolated from Arx-deficient embryos show a delayed differentiation in vivo together with an enhanced clonogenic capacity in vitro. We propose here that Arx acts as a novel positive regulator of embryonic myogenesis by synergizing with Mef2C and MyoD and by establishing an activating loop with Myogenin.