Jagged–Delta asymmetry in Notch signaling can give rise to a Sender/Receiver hybrid phenotype

Significance Notch signaling pathway plays crucial roles in cell-fate determination during embryonic development and cancer progression. According to the current paradigm, the Notch–Delta signaling leads to complementary cell-fate selection between two neighboring cells where one acts as Sender or Receiver. However, this picture is not complete because an additional ligand, Jagged, is involved in the Notch signaling. We devise a specific theoretical framework to decipher the functional role of Jagged. We find that the asymmetry between the modulations of Delta and Jagged leads to the existence of the previously unexplored possibility of a Sender–Receiver phenotype enabling two interacting cells to share a similar fate. This realization can provide important clues regarding embryonic development, wound healing, and how to target tumor–stroma signaling. Notch signaling pathway mediates cell-fate determination during embryonic development, wound healing, and tumorigenesis. This pathway is activated when the ligand Delta or the ligand Jagged of one cell interacts with the Notch receptor of its neighboring cell, releasing the Notch Intracellular Domain (NICD) that activates many downstream target genes. NICD affects ligand production asymmetrically––it represses Delta, but activates Jagged. Although the dynamical role of Notch–Jagged signaling remains elusive, it is widely recognized that Notch–Delta signaling behaves as an intercellular toggle switch, giving rise to two distinct fates that neighboring cells adopt––Sender (high ligand, low receptor) and Receiver (low ligand, high receptor). Here, we devise a specific theoretical framework that incorporates both Delta and Jagged in Notch signaling circuit to explore the functional role of Jagged in cell-fate determination. We find that the asymmetric effect of NICD renders the circuit to behave as a three-way switch, giving rise to an additional state––a hybrid Sender/Receiver (medium ligand, medium receptor). This phenotype allows neighboring cells to both send and receive signals, thereby attaining similar fates. We also show that due to the asymmetric effect of the glycosyltransferase Fringe, different outcomes are generated depending on which ligand is dominant: Delta-mediated signaling drives neighboring cells to have an opposite fate; Jagged-mediated signaling drives the cell to maintain a similar fate to that of its neighbor. We elucidate the role of Jagged in cell-fate determination and discuss its possible implications in understanding tumor–stroma cross-talk, which frequently entails Notch–Jagged communication.