Connective tissue fibroblasts and Tcf4 regulate myogenesis
Connective tissue fibroblasts and Tcf4 regulate myogenesis
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DOI：
10.1242/dev.057463
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发表时间：
2011-01-15
期刊：
影响因子：
4.6
通讯作者：
Kardon, Gabrielle
中科院分区：
文献类型：
--
作者：
Mathew, Sam J.;Hansen, Jody M.;Kardon, Gabrielle
肌肉及其结缔组织在胚胎和成人中紧密相连，这表明这些组织之间的相互作用对它们的发育至关重要。然而，由于缺乏标记结缔组织成纤维细胞的分子标记和遗传试剂，肌肉结缔组织的研究一直受到阻碍。在这里，我们证明了转录因子TCF4(转录因子7-样2；TCF7L2)在结缔组织成纤维细胞中强烈表达，并且TCF4(GFPCre)小鼠允许对这些成纤维细胞进行遗传操作。使用这种新试剂，我们发现结缔组织成纤维细胞对肌肉发生的两个方面起着关键的调节作用：肌肉纤维类型的发育和成熟。成纤维细胞通过刺激缓慢的肌球蛋白重链的表达(通过TCF4依赖的信号)促进缓慢的肌肉发生。此外，成纤维细胞通过抑制(通过TCF4依赖的信号)发育中的胚胎肌球蛋白的表达和促进(通过TCF4不依赖的机制)大的多核肌纤维的形成来促进从胎儿肌肉到成人肌肉的转换。此外，我们对TCF4功能的分析意外地揭示了肌肉纤维类型发育的内在调节的新机制。与其他纤维类型的内在调节因子不同，肌源性细胞中低水平的TCF4既促进了缓慢的肌肉发生，也促进了快速的肌肉发生，从而促进了肌肉纤维类型的全面成熟。因此，我们已经确定了调控肌肉发生的新的外在和内在机制。最重要的是，我们的数据首次证明结缔组织不仅对成年肌肉的结构和功能很重要，而且是肌肉祖细胞所在的生态位的重要组成部分，是肌肉发生的关键调节因素。
Muscle and its connective tissue are intimately linked in the embryo and in the adult, suggesting that interactions between these tissues are crucial for their development. However, the study of muscle connective tissue has been hindered by the lack of molecular markers and genetic reagents to label connective tissue fibroblasts. Here, we show that the transcription factor Tcf4 (transcription factor 7-like 2; Tcf7l2) is strongly expressed in connective tissue fibroblasts and that Tcf4(GFPCre) mice allow genetic manipulation of these fibroblasts. Using this new reagent, we find that connective tissue fibroblasts critically regulate two aspects of myogenesis: muscle fiber type development and maturation. Fibroblasts promote (via Tcf4-dependent signals) slow myogenesis by stimulating the expression of slow myosin heavy chain. Also, fibroblasts promote the switch from fetal to adult muscle by repressing (via Tcf4-dependent signals) the expression of developmental embryonic myosin and promoting (via a Tcf4-independent mechanism) the formation of large multinucleate myofibers. In addition, our analysis of Tcf4 function unexpectedly reveals a novel mechanism of intrinsic regulation of muscle fiber type development. Unlike other intrinsic regulators of fiber type, low levels of Tcf4 in myogenic cells promote both slow and fast myogenesis, thereby promoting overall maturation of muscle fiber type. Thus, we have identified novel extrinsic and intrinsic mechanisms regulating myogenesis. Most significantly, our data demonstrate for the first time that connective tissue is important not only for adult muscle structure and function, but is a vital component of the niche within which muscle progenitors reside and is a critical regulator of myogenesis.