Molecular Mechanisms of Myoblast Fusion

成肌细胞融合的分子机制

基本信息

批准号：
10928438
负责人：
Elizabeth H Chen
金额：
$ 20万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-18 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10928438
关键词：
Actins Adaptor Signaling Protein Address Anabolism Biological Assay Biological Metamorphosis Biology Bundling Cell Adhesion Molecules Cell fusion Cell membrane Cells Cicatrix Co-Immunoprecipitations Complex Cytoplasmic Tail Cytoskeletal Modeling Cytoskeleton Data Defect Degenerative Disorder Disease Drosophila genus Dynamin Ecdysone Embryo Embryonic Development Enzymes Exhibits F-Actin Fingers Genes Genetic Models Genetic Screening Genetic Transcription Grant Guanine Nucleotide Exchange Factors Guanosine Triphosphate Phosphohydrolases Health Human Invaded Life Link Liquid substance Mammals Mediating Membrane Membrane Fusion Molecular Molting Muscle Muscle Cells Muscle Development Muscle Fibers Muscle satellite cell Myoblasts Myopathy Natural regeneration Organ Phase Physical condensation Polymers Process Proteins Role SH3 Domains Series Signal Transduction Site Skeletal Muscle Structure Synapses System Testing Therapeutic Tissues Transcriptional Activation Wasps Work cellular transduction congenital myopathy ecdysone receptor embryo tissue experimental study fly hormonal signals in vivo insight muscle physiology muscle regeneration mutant myogenesis novel overexpression polymerization programs recruit response satellite cell steroid hormone

项目摘要

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.

项目概要骨骼肌是一种独特的器官，由多核肌纤维组成，每根肌纤维都是数百甚至数千个成肌细胞融合的产物不仅对成肌细胞融合很重要。尽管身体很大，但骨骼肌的发育对于基于卫星细胞的肌肉再生也至关重要。经过几十年的研究，人类成肌细胞融合的机制仍然很差对果蝇的研究揭示了对分子和分子的前所未有的见解。成肌细胞融合的细胞机制。果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特别相关的系统。我们的实验室发现了成肌细胞融合的一种新的细胞机制。融合由富含 F-肌动蛋白的足小体样结构 (PLS) 介导，该结构侵入相邻的融合尽管发现了 PLS，但与多个突出的手指配合导致融合孔形成。融合信号从细胞粘附分子转导至肌动蛋白细胞骨架仍不清楚。在这个提案中，我们将解决成肌细胞融合中两个长期存在的问题——成肌细胞如何融合程序在肌肉细胞中启动，以及融合信号如何从细胞粘附分子转导到我们将描述转录中令人惊讶的器官间蜕皮激素信号传导。激活肌肉特异性基因，研究相分离组织肌肉的机制融合机制，并阐明 Arf GEF 在调节融合机制肌动蛋白聚合中的功能我们的机制研究将带来对骨骼肌发育和突触的重要见解。再生。