Continuous Dynamic Modeling of Regulated Cell Adhesion: Sorting, Intercalation, and Involution.

Cell-cell adhesion is essential for tissue growth and multicellular pattern formation and crucial for the cellular dynamics during embryogenesis and cancer progression. Understanding the dynamical gene regulation of cell adhesion molecules (CAMs) responsible for the emerging spatial tissue behaviors is a current challenge because of the complexity of these nonlinear interactions and feedback loops at different levels of abstraction-from genetic regulation to whole-organism shape formation. To extend our understanding of cell and tissue behaviors due to the regulation of adhesion molecules, here we present a novel, to our knowledge, model for the spatial dynamics of cellular patterning, growth, and shape formation due to the differential expression of CAMs and their regulation. Capturing the dynamic interplay between genetic regulation, CAM expression, and differential cell adhesion, the proposed continuous model can explain the complex and emergent spatial behaviors of cell populations that change their adhesion properties dynamically because of inter- and intracellular genetic regulation. This approach can demonstrate the mechanisms responsible for classical cell-sorting behaviors, cell intercalation in proliferating populations, and the involution of germ layer cells induced by a diffusing morphogen during gastrulation. The model makes predictions on the physical parameters controlling the amplitude and wavelength of a cellular intercalation interface, as well as the crucial role of N-cadherin regulation for the involution and migration of cells beyond the gradient of the morphogen Nodal during zebrafish gastrulation. Integrating the emergent spatial tissue behaviors with the regulation of genes responsible for essential cellular properties such as adhesion will pave the way toward understanding the genetic regulation of large-scale complex patterns and shapes formation in developmental, regenerative, and cancer biology.