The Alternate Ligand Jagged Enhances the Robustness of Notch Signaling Patterns

Abstract

The Notch pathway, an example of juxtacrine signaling, is an evolutionary conserved cell-cell communication mechanism. It governs emergent spatiotemporal patterning in tissues during development, wound healing and tumorigenesis. Communication occurs when Notch receptors of one cell bind to either of its ligands, 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 cells to maintain similar fates (lateral induction). Here, by deriving and solving a reduced set of $12$ coupled ordinary differential equations for Notch-Delta-Jagged system on a hexagonal grid of cells, we determine the allowed states across different parameter sets. We also show that Jagged (at low dose) acts synergistically with Delta to enable more robust pattern formation by making the neighboring cell states more distinct from each other, despite its lateral induction property. Our findings extend our understanding of the possible synergistic role of Jagged with Delta which had been previously proposed through experiments and models in the context 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, perfectly ordered lateral inhibition pattern.