Interplay of Cell Shape and Division Orientation Promotes Robust Morphogenesis of Developing Epithelia

Epithelial cells acquire functionally important shapes (e.g., squamous, cuboidal, columnar) during development. Here, we combine theory, quantitative imaging, and perturbations to analyze how tissue geometry, cell divisions, and mechanics interact to shape the presumptive enveloping layer (pre-EVL) on the zebrafish embryonic surface. We find that, under geometrical constraints, pre-EVL flattening is regulated by surface cell number changes following differentially oriented cell divisions. The division pattern is, in turn, determined by the cell shape distribution, which forms under geometrical constraints by cell-cell mechanical coupling. An integrated mathematical model of this shape-division feedback loop recapitulates empirical observations. Surprisingly, the model predicts that cell shape is robust to changes of tissue surface area, cell volume, and cell number, which we confirm in vivo. Further simulations and perturbations suggest the parameter linking cell shape and division orientation contributes to epithelial diversity. Together, our work identifies an evolvable design logic that enables robust cell-level regulation of tissue-level development. [Display omitted] •Tissue geometry and cell mechanics constrain cell shapes in developing epithelia•Integrated mathematical model recapitulates dynamics of cell shape/number change•Interplay between cell shapes and division orientation ensures robust morphogenesis•Cell shape/division orientation relation may be tuned to give epithelial diversity A combination of imaging, mathematical theory, and embryological perturbations reveal that simple geometrical relations between tissue area, cell number, and cell volume restrict cell shapes and that shape in turn feeds back to control the number of cell divisions. This interplay ensures robust epithelial morphological development.