Feedback Interactions between Intracellular Contraction and Leading Edge Protrusion in Directed Cell Migration

Embryonic development depends on effective cell migration whose malfunction leads to abnormalities. Migration is the integrated outcome of a cycle of inter-connected component processes, namely protrusion, adhesion and contraction. Most, if not all, molecular details of these processes have been established. The major remaining challenge is to identify mechanisms that couple these processes in space and time. Compared to a relatively well-established interaction between protrusion and adhesion, however, there is no understanding as to how contraction and adhesion interact dynamically at the time scale of a single migration cycle, and whether these interactions affect protrusion through adhesion-protrusion coupling. The major hurdle that makes it challenging to investigate contraction- protrusion link is from technology: there is nearly no tool to quantify myosin II- based contraction in cytoskeletal network compared to numerous imaging approaches for characterization of protrusion - adhesion coupling. Here, we hypothesize that contraction dynamically modulates adhesion at a distance, which in turn promotes or inhibits protrusion via several redundant mechanical and signaling pathways. To test this hypothesis, we developed a continuum mechanical (CM) model to infer location and time of intracellular forces in migrating cells, which will be compared against high-resolution traction force microscopy (TFM) to obtain absolute force levels and infer material heterogeneity in the cytoskeleton. Preliminary results from Ptk1 cell wound-healing assay show that intracellular force field and traction force field are highly correlated, suggesting the feasibility of the absolute intracellular force level reconstruction. To establish the ‘information flow’ between contraction, adhesion and protrusion, we will use a correlation analysis of spontaneous fluctuations to show the coupling and information flow between them in unperturbed cells and in a cell where candidate molecules mediating the putative link between contraction and protrusion is slightly perturbed.