Grant: Project Grant

Cell-cell fusion is a regulated cellular process, occurring only in a few cell types, which is essential for development. During embryogenesis, the most frequent type of cell fusion is myoblast fusion, which joins the membranes of two different muscle cells to form a small muscle fibre. This process is repeated thousands of times until the muscle fibre reaches its correct size. Abnormal cell fusion is also a feature of muscle diseases, such as Limb Girdle Muscular Dystrophy. However, signalling cascades controlling cell fusion remain largely undefined. Therefore, the objective of this project is to uncover the mechanisms underlying cell fusion has it is not only important for basic biology, but will also contribute the knowledge essential for its manipulation in therapeutic settings, such as promoting regeneration in muscle diseases. Genetic studies in the fruit fly revealed the identity of some genes controlling fusion. Interestingly, the majority of them are involved in controlling the actin cytoskeleton, which is a structure that defines the cell's shape. We are expert in studying cytoskeletal dynamics. The conserved proteins governing cell fusion in vertebrates remained unknown until we discovered Dock1 as the first protein essential for myoblast fusion in mice. We next uncovered a signalling pathway essential for fusion composed of a receptor called Bai3, a signalling molecule called Elmo that binds Dock1, and their target Rac1. Here, we propose to characterize the mechanisms that ensure controlled activation of Bai3 at the right time for myoblast fusion to take place. Next, we outline experiments that will define the role of Elmo in myoblast fusion in muscle development and regeneration. Finally, we identified a protein that is selected by Rac1 to induce cell fusion. We found that this protein is tightly linked to a number of proteins involved in helping cells define their direction in a tissue, and we will determine how Tanc1 orchestrates cell fusion.