Molecular and cellular mechanisms of mammalian cell fusion

The fusion of one cell with another occurs in development, injury and disease. Despite the diversity of fusion events, five steps in sequence appear common. These steps include programming fusion-competent status, chemotaxis, membrane adhesion, membrane fusion, and post-fusion resetting. Recent advances in the field start to reveal the molecules involved in each step. This review focuses on some key molecules and cellular events of cell fusion in mammals. Increasing evidence demonstrates that membrane lipid rafts, adhesion proteins and actin rearrangement are critical in the final step of membrane fusion. Here we propose a new model for the formation and expansion of membrane fusion pores based on recent observations on myotube formation. In this model, membrane lipid rafts first recruit adhesion molecules and align with opposing membranes, with the help of a cortical actin "wall" as a rigid supportive platform. Second, the membrane adhesion proteins interact with each other and trigger actin rearrangement, which leads to rapid dispersion of lipid rafts and flow of a highly fluidic phospholipid bilayer into the site. Finally, the opposing phospholipid bilayers are then pushed into direct contact leading to the formation of fusion pores by the force generated through actin polymerization. The actin polymerization generated force also drives the expansion of the fusion pores. However, several key questions about the process of cell fusion still remain to be explored. The understanding of the mechanisms of cell fusion may provide new opportunities in correcting development disorders or regenerating damaged tissues by inhibiting or promoting molecular events associated with fusion.