Mechanisms of collective cell movement during embryonic heart development

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An outstanding question in biology is how cells coordinate their movements. Coordinated cell movements drive tissue development and repair, and also cause disease. A common feature of collective cell movements is the generation and transmission of mechanical forces. My research program develops novel quantitative microscopy and biophysical methods with the long-term objective of establishing the physical and molecular signals that coordinate cell behaviours in living animals. Our short-term goal for this proposal is to determine the mechanisms of cell movement and coordination during the early stages of heart development in the fruit fly Drosophila melanogaster. Heart development in vertebrates and invertebrates begins with the collective migration of two groups of cells from opposite sides of the embryo to form a tube. We use heart tube formation in Drosophila to model collective cell migration, as it is a stereotypical process involving two rows of 52 cardiac progenitors (cardioblasts) each, and it allows live imaging and genetic, pharmacological, and biophysical manipulations. We discovered that the movement of cardioblasts is not continuous, but rather consists of periodic steps forward. Importantly, we found that dynamic cytoskeletal protein networks flow periodically between the front and the back of each cardioblast, with each cycle corresponding with a cell step. In addition, we found a supracellular cable formed by the cytoskeletal protein actin and spanning the 52 cardioblasts in each row as they migrate. However, the mechanisms that govern cytoskeletal flows and cables, and the contributions of these networks to collective cell migration remain unclear. Here, we will (1) establish the role of dynamic cytoskeletal flows in cardioblast migration, and (2) define the contribution of the supracellular actin cable to collective cardioblast movements. To accomplish these aims, we will (3) develop quantitative microscopy, image analysis, and machine learning tools to monitor subcellular and supracellular cytoskeletal networks with high spatial and temporal resolution. Our tools will automate and thus accelerate the analysis of the images obtained, and will minimize human bias in the analysis. Our studies will reveal the mechanisms that control collective cell migration during heart tube formation in Drosophila. We will characterize a new mode of flow-driven cell movement, and a novel supracellular actin network that coordinates cardiac progenitor migration. The signals that regulate cytoskeletal dynamics are conserved across tissues and species. Thus, our findings will have direct implications for the general understanding of collective cell behaviours. Importantly, a group of talented trainees will also benefit from our research by receiving interdisciplinary training in cell and molecular biology, genetics, microscopy, image analysis and data science, all skills in high demand both in academic and industry settings.