Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 112, Issue 5, Pages E402-E409Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1416287112
Keywords
Notch signaling; Jagged; Fringe; cell signaling; developmental biology
Categories
Funding
- National Science Foundation (NSF) [PHY-1427654, NSF-MCB-1214457]
- Cancer Prevention and Research Institute of Texas (CPRIT)
- FAPESP [2013/14438-8]
- Keck Center for Interdisciplinary Bioscience Training of the Gulf Coast Consortia
- CPRIT [RP140113]
- NSF [CHE 1265929, 1152344]
- Welch Foundation [C1570]
- Tauber Family Funds
- Maguy-Glass Chair in Physics of Complex Systems
- Direct For Mathematical & Physical Scien
- Division Of Chemistry [1265929, 1152344] Funding Source: National Science Foundation
- Division Of Physics
- Direct For Mathematical & Physical Scien [1427654, 1308264] Funding Source: National Science Foundation
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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.
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