Cell-Cell Fusion in Development and Regeneration

Cell-cell fusion is a fascinating phenomenon in the development and physiology of multicellular organisms. It underlies diverse processes such as fertilization, skeletal muscle development and regeneration, placenta development, and the formation of osteoclasts in the bone and giant cells in immune response. My laboratory studies mechanisms underlying cell-cell fusion using a multifaceted approach including genetics, molecular biology, biochemistry, biophysics, live imaging, super-resolution microscopy and electron microscopy.

Starting with a forward genetic screen in Drosophila, we have identified multiple evolutionarily conserved core components of the myoblast fusion signaling cascade, and more importantly, discovered a novel cellular mechanism underlying myoblast fusion. We show that myoblast fusion is an asymmetric process in which one cell invades its fusion partner using actin-propelled membrane protrusions to promote fusion pore formation. Building on the insights we learned from myoblast fusion in vivo, we have reconstituted high-efficiency cell-cell fusion in an otherwise non-fusogenic, non-muscle cell line and uncovered a previously unrecognized function for the actin-propelled membrane protrusions in fusogen engagement. Similar actin-based membrane protrusions have since been observed in the fusion of mammalian muscle and non-muscle cells, suggesting that these invasive protrusions are used as a conserved and universal mechanism to promote cell-cell fusion. Using both Drosophila myoblast fusion and the reconstituted cell-fusion culture system, we 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 model for 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. Currently, we are identifying transmembrane fusogenic proteins and elucidating the functions of lipids, calcium signaling, membrane curvature and the mechanical principles in cell-cell fusion. Moreover, we are extrapolating our work in Drosophila to vertebrates and studying how cell-cell fusion is regulated in zebrafish muscle development and mouse muscle regeneration.