Direction Sensing During Collective Cell Migration

Collective cell migration is an important process not only in development but also in diseases. The Drosophila ovary, with its relatively simply structure, genetic tractability, and the compatibility with live imaging, is an excellent model for studying collective cell movements. My thesis consists of two parts. In the first part, I tried to understand the roles of adhesion in general, and E-cadherin in particular in collective cell migration. In the second part, I combined theoretical modeling with live imaging to probe the questions in collective cell movements that are hard to answer by experiments alone. E-cadherin is a major homophilic cell-cell adhesion molecule that inhibits motility of individual cells on matrix. However its contribution to migration of cells through cell-rich tissues is less clear. We developed an in vivo sensor of mechanical tension across E-cadherin molecules, which we combined with cell-type-specific RNAi, photo-activatable Rac, and morphodynamic profiling, to interrogate how E-cadherin contributes to collective migration of cells between other cells. Using the Drosophila ovary as a model, we found that adhesion between border cells and their substrate, the nurse cells, functions in a positive feedback loop with Rac and actin assembly to stabilize forward-directed protrusion and directionally persistent movement. Adhesion between individual border cells communicates direction from the lead cell to the followers. Adhesion between motile cells and polar cells holds the cluster together and polarizes each individual cell. Thus, E-cadherin is an integral component of the guidance mechanisms that orchestrate collective chemotaxis in vivo. A long-standing question in collective cell migration has been what the relative advantage might be of forming a cluster over migrating individually. Does an increase in size in collectively migrating cells enable them to sample the chemical gradient over a greater distance so that the difference between front and rear of a cluster would be more pronounced than for single cells? We combined theoretical modeling with experiments, and discovered that cluster size is positively related to migration speed. When cluster size reaches a certain limit however, speed no longer increases, likely due to the viscous drag from confining nurse cells. This is only the case for cells migrating in a physically constrained environment and thus is not apparent when cells are analyzed in vitro. The relationship between cluster size and migration velocity is predicted to be different for migration on a flat surface as compared to migration in a three-dimensional environment. Our data also suggest that the overall chemoattractant profile in the egg chamber is likely to be exponential, with highest concentration in the oocyte. Our findings reveal novel insights into collective chemotaxis, and demonstrate the power of combining theoretical modeling with experimentation