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.

项目摘要骨骼肌是由多核肌肉纤维组成的独特器官肌细胞融合不仅对骨骼肌发育，但对于基于卫星细胞的肌肉再生至关重要。尽管身体很大在数十年的研究中，人类成肌细胞融合的基础机制仍然很差理解。果蝇果蝇的研究表明，对分子和肌细胞融合的细胞机制。苍蝇和哺乳动物之间的惊人进化保护肌发生使果蝇成为研究体内成肌细胞融合的特别相关系统。最近的研究从我们的实验室中发现了肌细胞融合的基础的一种新型细胞机制。我们证明肌细胞融合是由富含F-肌动蛋白富集的Podosom类样结构（PLS）介导的，该结构（PLS）入侵了融合与多个突出的手指合作，导致融合孔的形成。尽管发现了PL，但如何融合信号从细胞粘附分子转换为肌动蛋白细胞骨架尚不清楚。在该建议，我们将在成肌细胞融合中解决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，以及如何将融合信号从细胞粘合分子转换为肌动蛋白细胞骨架。我们将表征转录中令人惊讶的器官间ecdysone信号传导激活肌肉特异性基因，研究相分离组织的机制融合机械，并阐明ARF GEF在控制肌动蛋白聚合在融合蛋白方面的功能突触。我们的机械研究将导致对骨骼肌发育和再生。