Molecular Mechanisms of Myoblast Fusion

点击翻译按钮获取中文摘要

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.