Mechanisms of cell-cell fusion in development and disease

Our lab is interested in understanding the mechanisms of cell-cell fusion. Although cell-cell fusion occurs in several specialized cell types, it is critical for the conception, development and physiology of multicellular organisms. For example, sperm and egg fusion initiates zygotic development; fusion between muscle cells (known as myoblasts) leads to the formation of multinucleated, contractile muscle fibers; and fusion between macrophages results in multinucleated giant cells during immune response. Cell-cell fusion has also been implicated in the formation of bone and placenta, tumorigenesis and stem cell-mediated tissue repair. Despite the diversity of cell types that undergo fusion, all cell-cell fusion events involve cell recognition, adhesion, and membrane merger, suggesting that shared molecular mechanisms may be used.

With the long-term goal of revealing the general mechanisms underlying cell-cell fusion, we focus our investigations on myoblast fusion, an indispensible step during muscle development and satellite cell-mediated muscle regeneration. We primarily use the model system Drosophila for our studies, since myoblast fusion in Drosophila is a highly conserved process, yet it is relatively simple and genetically tractable. Starting from a forward genetic screen, we first identified a collection of genes required for myoblast fusion in vivo, and subsequently placed these genes in a signaling cascade that transduces the fusion signal from the cell membrane to intracellular components. Interestingly, most of the "fusion genes" identified to date are linked to actin cytoskeleton remodeling, indicating an essential role of the actin cytoskeleton in cell membrane fusion.

Work in our lab in the past few years has revealed a surprising actin-based asymmetry at the sites of myoblast fusion. Contrary to the common belief that cell-cell fusion is a symmetrical process between two fusion partners, we have uncovered an actin-propelled, invasive podosome-like structure (PLS) protruding from one fusion partner into the other at the site of fusion. We further demonstrate that the dynamics of actin polymerization and the proper assembly of actin filaments within the PLS are critical for its invasion, which, in turn, promotes fusion pore initiation. These findings provide a new conceptual framework upon which future studies of cell-cell fusion can be built.

Currently, we continue to employ a multifaceted approach including genetics, molecular biology, biochemistry, immunohistochemistry, live imaging and electron microscopy to address the many unanswered questions of cell-cell fusion. For example, are invasive podosome-like structures required for fusing generic cells? How does a cell respond to PLS invasion? Is cell-cell fusion mediated by SNARE-like fusogens? Are the cellular mechanisms identified in Drosophila conserved in vertebrates? Answers to these questions will not only shed light on the fascinating biology of cell-cell fusion, but also provide basis for optimizing stem cell-mediated tissue regeneration in genetic and acquired diseases.