Lamellipodial wrinkles in fish keratocytes as markers of imperfect coordination between extension and retraction during cell migration

Cell migration involves the precise coordination between extension at the front of the cell and retraction at the rear. This coordination is particularly evident in fast moving cells such as fish keratocytes, where it leads to highly stable gliding motion, propelled at the front by broad, 0.1-0-2 μm thick lamellipodia. Transient uncoupling between extension and retraction can occur if the rear is temporarily stuck, which might eventually lead to cell shape instabilities. We have frequently observed in fish keratocytes the presence of lamellipodial radial wrinkles, detected by confocal, scanning electron and side-view microscopy as folds in the lamellipodium up to 2 μm in height. Using a linear finite elements analysis, we simulated the displacement of cells either with perfect coordination between extension and retraction or with the rear transiently stuck while the front continues extending, and we observed that in this last condition compression stresses arise in the lamellipodium which predict the formation of the observed pattern of lamellipodial wrinkles. In support of the numerical modeling findings, we observed that the transient halting of retraction at the rear using micromanipulation induced the formation of lamellipodial wrinkles in previously flat lamellipodia. The obtained results suggest that the conspicuous lamellipodial wrinkles observed in migrating fish keratocytes are the product of transient imbalances between front and rear displacements, and are therefore useful markers of the short scale dynamics of extension and retraction coordination during cell migration.