Grant: Project Grant

An outstanding question in biology is how cells coordinate their behaviours. For example, cells coordinate their movements to sculpt, repair, or invade tissues. A common feature of collective cell movements is the reorganization of the cell-cell adhesion complexes that keep cells together, and the cytoskeletal network of proteins that cells use to generate mechanical forces. However, the mechanisms that coordinate cell adhesion and cytoskeletal rearrangements during collective cell migration are not understood. We found that the protein Rap1, which acts as a molecular switch, is critical for both cell adhesion and cytoskeletal redistribution during collective cell movement. We will use the process of epidermal wound repair in fruit fly embryos to model coordinated cell movements and establish the mechanisms by which Rap1 orchestrates molecular rearrangements during collective cell migration. Because Rap1 is a well-known regulator of cell adhesion to the substrate, we will also investigate the role of cell-substrate adhesion in embryonic wound healing. Fruit fly embryos are transparent, allowing visualization of coordinated cell movements with high spatial and temporal detail; they are easy to manipulate genetically, and also with drugs and lasers; and over 75% of the genes involved in human disease exist in fruit flies. We will apply advanced microscopy and image analysis to track the distribution of molecules in living embryos; mathematical modelling to develop hypotheses about how changes in chemical or mechanical signals may affect cell adhesion and cytoskeletal protein dynamics and cell behaviour; and pharmacological, genetic and light-based manipulations to determine the signalling pathways by which Rap1 coordinates molecular rearrangements. Our results will increase our understanding of the signals that coordinate cell movements, and will enable subsequent efforts to manipulate cell migration for tissue engineering or cancer research applications.