Abstract
Notch pathway is an evolutionarily conserved cell–cell communication mechanism governing cell-fate during development and tumor progression. It is activated when Notch receptor of one cell binds to either of its ligand—Delta or Jagged—of another cell. Notch–Delta (ND) signaling forms a two-way switch, and two cells interacting via ND signaling adopt different fates—Sender (high ligand, low receptor) and Receiver (low ligand, high receptor). Notch–Delta–Jagged signaling (NDJ) behaves as a three-way switch and enables an additional fate—hybrid Sender/Receiver (S/R) (medium ligand, medium receptor). Here, by extending our framework of NDJ signaling for a two-cell system, we show that higher production rate of Jagged, but not that of Delta, expands the range of parameters for which both cells attain the hybrid S/R state. Conversely, glycosyltransferase Fringe and cis-inhibition reduces this range of conditions, and reduces the relative stability of the hybrid S/R state, thereby promoting cell-fate divergence and consequently lateral inhibition-based patterns. Lastly, soluble Jagged drives the cells to attain the hybrid S/R state, and soluble Delta drives them to be Receivers. We also discuss the critical role of hybrid S/R state in promoting cancer metastasis by enabling collective cell migration and expanding cancer stem cell (CSC) population.
Highlights
Biological systems comprise of many interconnected networks operating at different scales—from genetic and sub-cellular level to inter-cellular communication at tissue level to interactions among organ systems
We found that Notch–Delta–Jagged (NDJ) signaling circuit can behave as a three-way switch, giving rise to an additional hybrid Sender/Receiver (S/R)—(medium ligand, medium receptor) through which cells can both send and receive signals, and can adopt similar fates [25]
As opposed to the results largely pertaining to a single-cell system, here, we have extended that framework by focusing on a two-cell system to elucidate the effect of cis-inhibition, Fringe, production rates of Delta and Jagged, and soluble ligands in cell fate decisions mediated by the Notch signaling pathway, and cell-fate patterns observed at a tissue level
Summary
Content from this work may be used under the terms of the Creative Commons Attribution 3.0 licence. Any further distribution of Keywords: notch signaling, multistability, jagged, sender/receiver, cell–cell communication, pattern formation this work must maintain attribution to the Supplementary material for this article is available online author(s) and the title of the work, journal citation and DOI.
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