Modeling Epithelial Morphogenesis and Cell Rearrangement during Zebrafish Epiboly: Tissue Deformation, Cell-Cell Coupling, and the Mechanical Response to Stress

Morphogenesis in early development involves complex and extreme deformations in response to intra- and intercellular forces. Zebrafish epiboly, the spreading of the blastoderm to cover and engulf the large yolk cell, is a key early event that sets the stage for gastrulation, but is poorly understood. The enveloping layer (EVL), the thin squamous outer epithelium of the blastoderm, bound at its edges to the yolk cell by tight junctions, plays a central role. The marginal EVL cells receive through their tight junctions, forces generated in the yolk cell, and propagate those forces through the rest of the EVL; and the resulting EVL expansion is required for epiboly of the deep cells within the blastoderm. However, we don’t know how these exogenous forces are generated and regulated; several alternative force generation mechanisms have been proposed. In order to model their relative contributions, we need a mechanical model of the EVL capable of responding to such forces and undergoing the drastic deformation of epiboly. The expanding EVL more than doubles its surface area and experiences significant shear as it deforms from a thin cap at the pole to become a complete sphere, necessarily requiring extensive internal rearrangement. We constructed an agent-based model of the EVL and its response to exogenous forces using the center-based simulation framework, Tissue Forge. Our model captures the large viscoelastic deformation of the EVL by cell rearrangement, and incorporates algorithmic strategies to accommodate these dynamic changes while maintaining tissue cohesion. Features observed in living embryos, such as the straightening of the initially ragged leading edge, also emerge in the model. We identified two key components required for realistic epiboly in the model: first, a mechanism to enable tissue remodeling by cell rearrangement without tearing the tissue, and second, a regulatory negative feedback on the forces driving EVL expansion, to synchronize the advancement of the EVL margin. We discuss the implications of these findings for the behavior of living EVL and the mechanisms that drive epiboly.