Collective cell migration is a fundamental process required for tissue development, wound repair and cancer invasion. Gastrulation, the formation of the three germ layers is characterized by collectively migrating cells that anteriorly form the prechordal plate and posteriorly shape the notochord, the major skeletal element of the developing embryo. The cellular process leading to the formation of the rod-shaped notochord during collective cell migration of the mesodermal plate is unknown.
We found Protocadherin18a (Pcdh18a), a member of the cadherin superfamily as a novel regulator of cohesive cell migration during zebrafish gastrulation. We show that Pcdh18a is expressed in the notochord tip cells (NTCs) and controls the adhesive and migratory behavior of this cell group. Enhanced adhesiveness and fast migration of the NTCs are required for formation of the 3D structure of the posteriorly-located notochord. Migrating cells rapidly adhere and de-adhere in order to translocate over their substrate. We indeed find that Pcdh18a regulates endocytosis of the E-cad/Fzd7 adhesion complexes in E-cad positive mouse fibroblasts, in human cervical cancer cells and during zebrafish gastrulation. Consistently, endocytic blockade in Pcdh18a positive cells reduces cell migration in vitro and in vivo. In summary, we conclude that during gastrulation, Pcdh18a positive NTCs organize the shape of the notochord, independently of cell migration events in the lateral plate mesoderm.