Establishment of Signaling Interactions with Cellular Resolution for Every Cell Cycle of Embryogenesis.

Intercellular signaling interactions play a key role in breaking fate symmetry during animal development. Identification of signaling interactions at cellular resolution is technically challenging, especially in a developing embryo. Here, we develop a platform that allows automated inference and validation of signaling interactions for every cell cycle of embryogenesis. This is achieved by the generation of a systems-level cell contact map, which consists of 1114 highly confident intercellular contacts, by modeling analysis and is validated through cell membrane labeling coupled with cell lineage analysis. We apply the map to identify cell pairs between which a Notch signaling interaction takes place. By generating expression patterns for two ligands and two receptors of the Notch signaling pathway with cellular resolution using the automated expression profiling technique, we are able to refine existing and identify novel Notch interactions during embryogenesis. Targeted cell ablation followed by cell lineage analysis demonstrates the roles of signaling interactions during cell division in breaking fate symmetry. Finally, we describe the development of a website that allows online access to the cell-cell contact map for mapping of other signaling interactions by the community. The platform can be adapted to establish cellular interactions from any other signaling pathway.