Wednesday, April 2, 2025
4/2/2025
Molecular Mechanisms of Myoblast Fusion - PROJECT SUMMARY Myoblast fusion, during which mononucleated myoblasts fuse to form multinucleate, contractile muscle fibers, is essential for skeletal muscle development and regeneration. Certain congenital myopathies are characterized by minute myofibers, suggesting that myoblast fusion may be compromised in these conditions. Thus, investigating the mechanisms of myoblast fusion is imperative not only for understanding muscle biology in development and regeneration, but also for developing novel therapeutic approaches for muscle diseases. In the past two decades, the fruit fly Drosophila has been used as a premier genetic and cell biological model to study myoblast fusion in vivo. These studies have uncovered a handful of evolutionarily conserved regulators of myoblast fusion and a novel cellular mechanism. My lab has shown that myoblast fusion is an asymmetric process in which one cell invades its fusion partner using F-actin-propelled membrane protrusions to promote membrane fusion. Similar invasive protrusions have since been observed in the fusion of vertebrate muscle and non-muscle cells, suggesting that these invasive protrusions are used as a conserved and universal mechanism to promote cell-cell fusion. Furthermore, we have discovered a mechanosensory response in the receiving fusion partner and demonstrated that mechanical tension is a driving force for cell-cell fusion. Our work to date has established a biophysical framework for understanding cell-cell fusion – the interplay between the pushing forces and the resisting forces from the two fusion partners at the fusogenic synapse brings the apposing cell membranes into close proximity to facilitate fusogen engagement and membrane fusion. Despite the critical role for actin polymerization in myoblast fusion and the identification of WASP family of actin nucleation-promoting factors (NPFs) required for this process, how the invading fusion partner rapidly generate a large amount of actin filaments at the fusogenic synapse and how these actin filaments are coupled to the cell membrane to effectively propel invasive protrusions remain poorly understood. In this grant, we will take a multifaceted approach, including genetics, cell biology, molecular biology, and biochemistry, to investigate these questions, aiming to obtain a deeper mechanistic understanding of myoblast fusion. We propose the following Specific Aims. In Specific Aim I, we will investigate the role of phase separation in enriching the actin polymerization machinery at the fusogenic synapse. In Specific Aim II, we will investigate the role of Arf GEF Loner and Arf GTPases in upregulating actin polymerization in myoblast fusion. In Specific Aim III, we will investigate the role of APC/C- Fzr and its downstream target Anillin in myoblast fusion.
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