Skeletal muscle is a prime target organ for gene therapy, as engineered myoblasts can be introduced to fuse with mature muscle, forming a stable hybrid organ within the adults. The ability of injected satellite cells to fuse with myofibers directly affects the efficacy of cell-based gene therapy. Therefore, understanding the mechanisms controlling myoblast fusion promises to offer novel therapeutic possibilities in the future. We are using the fruit fly Drosophila as a genetic model to study the molecular mechanisms of myoblast fusion. Studies in recent years have revealed that many of the cellular and molecular events involved in muscle development are evolutionarily conserved between fly and vertebrates. This conservation has made it possible to dissect muscle differentiation using Drosophila genetics and to uncover essential genes required for myoblast fusion in flies and vertebrates. In a genetic screen for mutants in muscle development, we have identified a number of new loci required for myoblast fusion. To date, we have molecularly characterized two genes, antisocial and loner. Studies of these and other fusion genes have begun to reveal a signaling cascade controlling myoblast fusion. Antisocial is a novel adaptor protein that is localized to subcellular sites of fusion and relays the fusion signal from cell membrane to actin cytoskeleton. Loner, a guanine nucleotide exchange factor for ARF6, can also be recruited to sites of fusion. The goal of this project is to address two major questions concerning the mechanisms of myoblast fusion. First, how are fusion proteins recruited to sites of fusion by transmembrane receptors? Second, how is actin cytoskeletal rearrangement achieved during myoblast fusion? We propose a series of experiments to investigate the mechanisms by which Ants and Loner are targeted to sites of fusion.
In Specific Aim I, we will identify domain(s) in Ants that are responsible for its localization to sites of fusion.
In Specific Aim II, we will use biochemical and yeast two- hybrid approaches to isolate the intermediary protein(s) responsible for recruiting Loner to sites of fusion.
In Specific Aim III, we propose the identification and characterization of a new component of the myoblast fusion machinery. We will examine its phenotype, localization, and interactions with known fusion proteins as well as with components of the actin cytoskeleton.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
Project #
Application #
Study Section
Skeletal Muscle and Exercise Physiology Study Section (SMEP)
Program Officer
Boyce, Amanda T
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Johns Hopkins University
Schools of Medicine
United States
Zip Code
Duan, Rui; Kim, Ji Hoon; Shilagardi, Khurts et al. (2018) Spectrin is a mechanoresponsive protein shaping fusogenic synapse architecture during myoblast fusion. Nat Cell Biol 20:688-698
Shi, Jun; Bi, Pengpeng; Pei, Jimin et al. (2017) Requirement of the fusogenic micropeptide myomixer for muscle formation in zebrafish. Proc Natl Acad Sci U S A 114:11950-11955
Kim, Ji Hoon; Jin, Peng; Duan, Rui et al. (2015) Mechanisms of myoblast fusion during muscle development. Curr Opin Genet Dev 32:162-70
Kim, Ji Hoon; Ren, Yixin; Ng, Win Pin et al. (2015) Mechanical tension drives cell membrane fusion. Dev Cell 32:561-73
Shilagardi, Khurts; Li, Shuo; Luo, Fengbao et al. (2013) Actin-propelled invasive membrane protrusions promote fusogenic protein engagement during cell-cell fusion. Science 340:359-63
Duan, Rui; Jin, Peng; Luo, Fengbao et al. (2012) Group I PAKs function downstream of Rac to promote podosome invasion during myoblast fusion in vivo. J Cell Biol 199:169-85
Jin, Peng; Duan, Rui; Luo, Fengbao et al. (2011) Competition between Blown fuse and WASP for WIP binding regulates the dynamics of WASP-dependent actin polymerization in vivo. Dev Cell 20:623-38
Sens, Kristin L; Zhang, Shiliang; Jin, Peng et al. (2010) An invasive podosome-like structure promotes fusion pore formation during myoblast fusion. J Cell Biol 191:1013-27