In vivo CCM requires a basal level of cell–cell adhesion. (A) Dispersion assay of controls (green curve) or control cells cultured in low calcium/magnesium conditions (orange curve), or cells expressing N-cadherin dominant-negative (N-cadh ΔCyto, blue curve) analyzed by triangulation. Control versus low Ca²⁺/Mg²⁺, n = 11 explants from four independent experiments. Student’s two-tailed t test: ***, P = 0.0093. Control versus N-CadhΔCyto, n = 15 explants from four independent experiments. ***, P = 0.0094. Error bars indicate SD. (B–D) Analysis of NC migration after inhibition of N-cadherin using a Morpholino (B), overexpression of deletion constructs lacking the cytoplasmic domain (C), and a β-catenin binding domain (D). Asterisks indicate eyes. (E) Distance of NC migration from experiments shown in B–D. 77 embryos were analyzed. One-way ANOVA: P < 0.0001. Individual comparisons: **, P < 0.01; ***, P < 0.001. Error bars indicate SD. (F–I) Model of NC migration. (F) NC cells progressively dissociate while migrating toward the ventral side of the head. The color code indicates the range of partial mesenchymal phenotypes with a transition from an early EMT/solid-like (red) to a late-EMT/fluid-like (green) phenotype. (G) At the onset of EMT, cells are motile but too tightly attached to one another to invade other tissues, as they express high levels of N-cadherin in the membrane. (H) After cell–cell dissociation triggered by LPA/LPAR2–dependent N-cadherin internalization, NC cells can migrate and invade other tissues. (I) Dramatic reduction of cell–cell adhesion promotes a fully mesenchymal phenotype that favors dispersion of individual cells in vitro but impairs directional migration in vivo.