Grant: Project Grant

An outstanding question in biology is how cells coordinate their behaviours. Cells coordinate their movements to sculpt, repair, or invade tissues. A common feature of collective cell movements in development, repair, and disease is the reorganization of the cytoskeleton, the network or proteins that cells use to generate mechanical forces. However, the mechanisms that promote cytoskeletal redistribution during collective cell migration are not understood. We found that highly reactive, oxygen-containing molecules (reactive oxygen species) are critical for cytoskeletal rearrangements during collective cell movement. In addition, we and others showed that cytoskeletal proteins can be regulated by the mechanical forces sustained by cells in living animals. We will use the process of epidermal wound repair in fruit fly embryos to model collective cell movements and establish the basic molecular and physical mechanisms of cytoskeletal reorganization during collective cell migration. 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 cytoskeletal protein dynamics and cell behaviour; and pharmacological, genetic and biophysical manipulations to test modelling predictions and determine the molecular pathways by which reactive oxygen species and mechanical forces affect cytoskeletal dynamics. Our results will reveal the mechanochemical signals that coordinate cell movements, and will enable subsequent efforts to manipulate cell migration for tissue engineering or cancer research applications.