Spatiotemporal changes in epithelial cell sizes—or epithelial cell size dynamics (ECD)—during morphogenesis entail interplay between two opposing forces: cell contraction via actomyosin cytoskeleton and cell expansion via cell–cell adhesion. Cell–cell adhesion–based ECD, however, has not yet been clearly demonstrated. For instance, changing levels of homophilic E-cadherin-based cell–cell adhesion induce cell sorting, but not ECD. Here we show that cell-expansive forces of heterophilic cell–cell adhesion regulate ECD: higher cell–cell adhesion results in cell size enlargement. Thus, ECD during morphogenesis in the heminotal epithelia of Drosophila pupae leading to thorax closure corresponds with spatiotemporal gradients of two heterophilic atypical cadherins—Fat (Ft) and Dachsous (Ds)—and the levels of Ft–Ds heterodimers formed concomitantly. Our mathematical modeling and genetic tests validate this mechanism of dynamic heterophilic cell–cell adhesion–based regulation of ECD. Conservation of these atypical cadherins suggests a wider prevalence of heterophilic cell–cell adhesion–based ECD regulation during animal morphogenesis.
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