SUMMARY Elucidation of complex phenotypes for mechanistic insights presents a significant challenge in systems biology. We report a strategy to automatically infer mechanistic models of cell fate differentiation based on live-imaging data. We use cell lineage tracing and combinations of tissue-specific marker expression to assay progenitor cell fate and detect fate changes upon genetic perturbation. Based on the cellular phenotypes, we further construct a model for how fate differentiation progresses in progenitor cells and predict cell-specific gene modules and cell-to-cell signaling events that regulate the series of fate choices. We validate our approach in C. elegans embryogenesis by perturbing 20 genes in over 300 embryos. The result not only recapitulates current knowledge but also provides insights into gene function and regulated fate choice, including an unexpected self-renewal. Our study provides a powerful approach for automated and quantitative interpretation of complex in vivo information.

BackgroundGastrulation is a key transition in embryogenesis; it requires self-organized cellular coordination, which has to be both robust to allow efficient development and plastic to provide adaptability. Despite the conservation of gastrulation as a key event in Metazoan embryogenesis, the morphogenetic mechanisms of self-organization (how global order or coordination can arise from local interactions) are poorly understood.ResultsWe report a modular structure of cell internalization in Caenorhabditis elegans gastrulation that reveals mechanisms of self-organization. Cells that internalize during gastrulation show apical contractile flows, which are correlated with centripetal extensions from surrounding cells. These extensions converge to seal over the internalizing cells in the form of rosettes. This process represents a distinct mode of monolayer remodeling, with gradual extrusion of the internalizing cells and simultaneous tissue closure without an actin purse-string. We further report that this self-organizing module can adapt to severe topological alterations, providing evidence of scalability and plasticity of actomyosin-based patterning. Finally, we show that globally, the surface cell layer undergoes coplanar division to thin out and spread over the internalizing mass, which resembles epiboly.ConclusionsThe combination of coplanar division-based spreading and recurrent local modules for piecemeal internalization constitutes a system-level solution of gradual volume rearrangement under spatial constraint. Our results suggest that the mode of C. elegans gastrulation can be unified with the general notions of monolayer remodeling and with distinct cellular mechanisms of actomyosin-based morphogenesis.