RhoE controls myoblast alignment prior fusion through RhoA and ROCK
RhoE controls myoblast alignment prior fusion through RhoA and ROCK
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DOI：
10.1038/cdd.2008.34
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发表时间：
2008-08-01
影响因子：
12.4
通讯作者：
Gauthier-Rouviere, C.
中科院分区：
文献类型：
--
作者：
Fortier, M.;Comunale, F.;Gauthier-Rouviere, C.
骨骼肌成肌细胞向多核肌管的分化是一个由多个信号通路协调的多步骤过程。Rho小G蛋白家族在成肌诱导和成肌细胞融合过程中发挥着关键作用。我们在这里报告说，在C2 C12成肌细胞，RhoE，这个家族的非典型成员的表达，增加，直到成肌细胞融合之前恢复其基础水平，一旦融合发生。我们发现RhoE在融合前在细长的成肌细胞中积累，并且在损伤诱导的骨骼肌再生过程中其表达也增加。此外，虽然RhoE不是肌生成诱导所必需的，但它对于成肌细胞在融合前的伸长和排列以及M-钙粘蛋白在细胞-细胞接触位点的表达和积累是必不可少的。缺乏RhoE的成肌细胞在成肌细胞融合开始时存在缺陷的p190 RhoGAP激活和RhoA抑制。RhoE还与RhoA效应物Rho相关激酶（ROCK）I相互作用，其活性必须下调以允许成肌细胞融合。一致地，我们表明RhoA或ROCK的药理学失活恢复了RhoE缺陷成肌细胞中的成肌细胞融合。成肌细胞融合前RhoE的生理上调是导致融合过程所需的RhoA和ROCKI活性降低的原因。因此，我们得出结论，RhoE是成肌细胞融合的重要调节因子。
Differentiation of skeletal myoblasts into multinucleated myotubes is a multi-step process orchestrated by several signaling pathways. The Rho small G protein family plays critical roles both during myogenesis induction and myoblast fusion. We report here that in C2C12 myoblasts, expression of RhoE, an atypical member of this family, increases until the onset of myoblast fusion before resuming its basal level once fusion has occurred. We show that RhoE accumulates in elongated, aligned myoblasts prior to fusion and that its expression is also increased during injury-induced skeletal muscle regeneration. Moreover, although RhoE is not required for myogenesis induction, it is essential for myoblast elongation and alignment before fusion and for M-cadherin expression and accumulation at the cell-cell contact sites. Myoblasts lacking RhoE present with defective p190RhoGAP activation and RhoA inhibition at the onset of myoblast fusion. RhoE interacts also with the RhoA effector Rho-associated kinase (ROCK) I whose activity must be downregulated to allow myoblast fusion. Consistently, we show that pharmacological inactivation of RhoA or ROCK restores myoblast fusion in RhoE-deficient myoblasts. RhoE physiological upregulation before myoblast fusion is responsible for the decrease in RhoA and ROCKI activities, which are required for the fusion process. Therefore, we conclude that RhoE is an essential regulator of myoblast fusion.