Cadherin-Dependent Cell Morphology in an Epithelium: Constructing a Quantitative Dynamical Model

Cells in the Drosophila retina have well-defined morphologies that are attained during tissue morphogenesis. We present a computer simulation of the epithelial tissue in which the global interfacial energy between cells is minimized. Experimental data for both normal cells and mutant cells either lacking or misexpressing the adhesion protein N-cadherin can be explained by a simple model incorporating salient features of morphogenesis that include the timing of N-cadherin expression in cells and its temporal relationship to the remodeling of cell-cell contacts. The simulations reproduce the geometries of wild-type and mutant cells, distinguish features of cadherin dynamics, and emphasize the importance of adhesion protein biogenesis and its timing with respect to cell remodeling. The simulations also indicate that N-cadherin protein is recycled from inactive interfaces to active interfaces, thereby modulating adhesion strengths between cells. Author Summary: Tissues are intricate, heterogeneous systems, consisting of individual cells whose shapes and relative positions are of great importance to the tissue's function, as well as to its formation during morphogenesis. To make progress in our understanding of the formation of organs, their malfunction, and their therapeutic replacement in regenerative medicine, it is crucial to elucidate the connection between shape and function. We have developed a quantitative mechanical model of an epithelial tissue, the retina of Drosophila, and compare the modeling results with experimental data. The model successfully predicts shape changes induced by different expression levels of cell-cell adhesion molecules. Furthermore, the model gives new insight into the changes a tissue undergoes during morphogenesis. Comparing simulations and experiments, we are able to accept or reject different hypotheses about morphogenetic dynamics. In this way, we can identify the time course of adhesion molecule synthesis and of cell-cell contact, as well as gain new insight into the regulation of adhesion strength. Given the prominent role of adhesion in wound healing, cancer research, and many other fields, our fundamental work introduces a novel modeling tool of universal applicability and importance.