The Alternate Ligand Jagged Enhances the Robustness of Notch Signaling Patterns

Notch signaling pathway is an evolutionary conserved cell-cell communication mechanism. It governs emergent spatiotemporal patterning in a tissue during development, wound healing and tumorigenesis; when Notch receptor of one cell binds to either of its ligand, Delta/Jagged of neighboring cell. In general, Delta-mediated signaling drives neighboring cells to have an opposite fate (lateral inhibition) whereas Jagged-mediated signaling drives all the cells to maintain similar fate (lateral induction). By solving a system of 12 coupled ordinary differential equations, we calculate the phase space across different parameters for hexagonal ordered states. We quantify how the number of Sender (high ligand, low receptor) cells in a disordered pattern increases, as production rate of Jagged increases. We also show that, Jagged (at low dose) acts synergistically with Delta to get more refined robust pattern despite of its lateral induction property, due to competition with Delta in binding with Notch, as experimentally observed in case of chick inner ear development. Finally, we show that how Jagged can help to expand the bistable (both Uniform and Hexagon phases are stable) region, where a local perturbation can spread over time in a ordered manner to create a biologically relevant, defect-free lateral induction pattern.