A molecular base for cell sorting at embryonic boundaries: contact inhibition of cadherin adhesion by ephrin/ Eph-dependent contractility

The mechanism responsible for subdividing the embryo into individual tissues is a fundamental, yet still poorly understood, question in developmental biology. Various general hypotheses have been proposed, involving differences in cell adhesion, contractility, or contact-mediated repulsion. However, the key parameter in tissue separation, i.e., the regulation of cadherin-based adhesion at the boundary, has not yet been investigated. We show that cadherin clustering is specifically inhibited at the vertebrate notochord-presomitic mesoderm boundary, preventing formation of adhesive bonds between cells of the two different types. This local regulation depends on differentially expressed ephrins and Eph receptors, which increase cell contractility and generate a membrane blebbing-like behavior along the boundary. Inhibiting myosin activity is sufficient to induce cadherin clustering and formation of stable contacts across the boundary, causing notochord and presomitic tissues to fuse. Local inhibition of cadherin adhesion explains how sharp separation can be achieved in response to cell-cell contact signals.