Molecular Mechanisms of Myoblast Fusion

项目摘要 骨骼肌是一种独特的器官，由多核肌纤维组成，每一个肌纤维都是骨骼肌。 数百甚至数千个成肌细胞融合的产物。成肌细胞融合不仅对 骨骼肌发育，但也是关键的卫星细胞为基础的肌肉再生。尽管身体很大 在过去几十年的研究中，人类成肌细胞融合的机制仍然很差， 明白对果蝇的研究揭示了前所未有的对分子和 成肌细胞融合的细胞机制。苍蝇和哺乳动物之间惊人的进化保守性 肌发生使果蝇成为研究体内成肌细胞融合的一个特别相关的系统。最近的研究 发现了一种新的成肌细胞融合的细胞机制我们发现成肌细胞 融合是由富含F-肌动蛋白的足状体样结构（PLS）介导的，其侵入并置融合 与多个膨胀的指状物配对，导致融合孔形成。尽管发现了PLS， 融合信号从细胞粘附分子转导到肌动蛋白细胞骨架仍然不清楚。在 在这个提议中，我们将解决成肌细胞融合中两个长期存在的问题--成肌细胞融合如何 程序是在肌肉细胞中启动的，以及融合信号是如何从细胞粘附分子转导到 肌动蛋白细胞骨架我们将描述令人惊讶的器官间蜕皮激素信号的转录 肌肉特异性基因的激活，研究相分离组织肌肉的机制。 融合机制，并阐明功能的Arf GEF在调节肌动蛋白聚合在融合 突触我们的机制研究将导致对骨骼肌发育的重要见解， 再生

PROJECT SUMMARY Skeletal muscle is a unique organ that is composed of multinucleate muscle fibers, each of which is the product of fusion of hundreds or even thousands of myoblasts. Myoblast fusion is not only important for skeletal muscle development, but also critical for satellite cell-based muscle regeneration. Despite a large body of studies over several decades, the mechanisms underlying myoblast fusion in humans remain poorly understood. Studies in the fruit fly Drosophila have revealed unprecedented insights into the molecular and cellular mechanisms of myoblast fusion. The striking evolutionary conservation between fly and mammalian myogenesis makes Drosophila a particularly relevant system to study myoblast fusion in vivo. Recent studies from our lab have uncovered a novel cellular mechanism underlying myoblast fusion. We show that myoblast fusion is mediated by F-actin-enriched podosome-like structure (PLS), which invades the apposing fusion partner with multiple protrusive fingers leading to fusion pore formation. Despite the discovery of the PLS, how the fusion signal is transduced from the cell adhesion molecule to the actin cytoskeleton remains unclear. In this proposal, we will address two long-standing questions in myoblast fusion – how the myoblast fusion program is initiated in muscle cells and how the fusion signal is transduced from the cell adhesion molecules to the actin cytoskeleton. We will characterize the surprising inter-organ ecdysone signaling in the transcriptional activation of muscle-specific genes, investigate the mechanism by which phase separation organizes the fusion machinery, and elucidate the function of an Arf GEF in regulating actin polymerization at the fusogenic synapse. Our mechanistic studies will lead to significant insights into skeletal muscle development and regeneration.