Elizabeth H. Chen
Department of Molecular Biology and Genetics
The Johns Hopkins University
725 N. Wolfe Street
Baltimore, MD 21205
2006 Searle Scholar
Molecular mechanisms of myoblast fusion
Cell-cell fusion is critical to the successful development of multicellular organisms. It is required for events as diverse as fertilization, formation of bone and placenta, and myogenesis. Despite the variety of cell types that undergo fusion, the cellular events involved in this process, including cell recognition, adhesion and membrane merger, are common to all cell-cell fusion events, which suggests that shared molecular mechanisms might be used. My lab is using myoblast fusion in Drosophila as a model system to study the general mechanisms of cell-cell fusion. Myoblast fusion, the process in which mononucleated myoblasts fuse to form multinucleated muscle fibers, is a characteristic step during myogenesis. The relatively simple musculature, rapid developmental time, conserved cellular events during fusion and the powerful genetic tools available in Drosophila make it an ideal system to dissect myoblast fusion in vivo.
In Drosophila, myoblast fusion commences in a highly orchestrated manner. Initially, a subset of myoblasts, called muscle founder cells, acts as seeds that attract neighboring fusion-competent myoblasts. Subsequently, these two types of cells align with each other, and eventually the apposing plasma membranes coalesce, allowing fusion. Successive rounds of fusion lead to the formation of multinucleated myotubes. We have taken a systematic genetic approach to study myoblast fusion with the ultimate goal of identifying all genes required for this complicated cellular process. So far we have identified 11 new loci required for myoblast fusion, among which two genes, antisocial and loner, have been characterized using molecular, biochemical and cell biological approaches. Antisocial is an adaptor protein that relays the fusion signal from the membrane to the cytoskeleton. Loner is a guanine nucleotide exchange factor for the small GTPase ARF6, which in turn regulates cytoskeleton rearrangement during myoblast fusion. Further characterization of these and additional genes from the genetic screen will shed light on the signaling network underlying myoblast fusion and other cell-cell fusion events. Given the evolutionary conservation of many signaling cascades, studies of myoblast fusion in Drosophila are likely to provide insights into mammalian myogenesis, and may have implications for therapeutic approaches to human myopathies.