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.