Multistability in Notch-Jagged-Delta signaling pathway (original) (raw)
Operating principles of Notch–Delta–Jagged module of cell–cell communication
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 viaNDsignaling 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.
Cis-interactions between Notch and Delta generate mutually exclusive signalling states
2010
The Notch-Delta signaling pathway enables communication between neighboring cells during development 1. It plays a critical role in the formation of 'fine-grained' patterns, generating distinct cell fates among groups of initially equivalent neighboring cells, and in sharply delineating neighboring regions in developing tissues 2,3,4,5. The Delta ligand has been shown to have two activities: it trans-activates Notch in neighboring cells, and cis-inhibits Notch in its own cell. However, it remains unclear how Notch integrates these two activities and how the resulting system facilitates pattern formation. To address these questions, we developed a quantitative timelapse microscopy platform for analyzing Notch-Delta signaling dynamics in individual mammalian cells. By controlling both cis-and trans-Delta levels, and monitoring the dynamics of a Notch reporter, we measured the combined cis-trans input-output relationship for the Notch-Delta system. The data revealed a striking difference between the response of Notch to trans-and cis-Delta: While the response to trans-Delta is graded, the response to cis-Delta exhibits a sharp, switch-like response at a fixed threshold, independent of trans-Delta. We developed a simple mathematical model that shows how these behaviors emerge from the mutual inactivation of Notch and Delta proteins. This interaction generates an ultrasensitive switch between mutually exclusive sending (high Delta / low Notch) and receiving (high Notch / low Delta) signaling states. At the multicellular level, this switch can amplify small differences between neighboring cells even without transcription-mediated feedback. This Notch-Delta signaling switch facilitates the formation of sharp boundaries and lateral inhibition patterns in models of development, and provides insight into previously unexplained mutant behaviors. Notch and Delta are single-pass transmembrane protein families found in metazoan species. Delta in one cell can bind to, and transactivate, Notch in a neighboring cell. This interaction results in proteolytic release of the Notch intracellular domain (ICD), which translocates to the nucleus and activates target genes 6 (Fig. 1A). Delta also plays a second role, inhibiting Notch activity in its own cell (cis-inhibition) 7,8,9,10. Cis-inhibition has been shown to involve direct interaction of the two proteins 11 , but current understanding is incomplete 12. In order to understand how levels of cis-and trans-Delta are integrated by the Notch pathway (Fig. 1B), we constructed cell lines that allowed us to independently modulate the Author Contributions DS and MBE designed the research. DS, LAS, MEF, and GAA built cell lines and performed experiments. DS, AL, LL, JGO, and MBE performed data analysis and mathematical modeling. DS and MBE wrote the manuscript with substantial input from the other authors.
Jagged–Delta asymmetry in Notch signaling can give rise to a Sender/Receiver hybrid phenotype
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.
Cis Interactions between Notch and Delta Generate Mutually Exclusive Signaling States
2016
The Notch-Delta signaling pathway enables communication between neighboring cells during development1. It plays a critical role in the formation of ‘fine-grained ’ patterns, generating distinct cell fates among groups of initially equivalent neighboring cells, and in sharply delineating neighboring regions in developing tissues 2,3,4,5. The Delta ligand has been shown to have two activities: it trans-activates Notch in neighboring cells, and cis-inhibits Notch in its own cell. However, it remains unclear how Notch integrates these two activities and how the resulting system facilitates pattern formation. To address these questions, we developed a quantitative time-lapse microscopy platform for analyzing Notch-Delta signaling dynamics in individual mammalian cells. By controlling both cis- and trans-Delta levels, and monitoring the dynamics of a Notch reporter, we measured the combined cis-trans input-output relationship for the Notch-Delta system. The data revealed a striking differ...
Diversity of fate outcomes in cell pairs under lateral inhibition
2015
Cell fate determination by lateral inhibition via Notch/Delta signalling has been extensively studied. Most formalised models consider Notch/Delta interactions in fields of cells, with parameters that typically lead to symmetry breaking of signalling states between neighbouring cells, commonly resulting in salt-and-pepper fate patterns. Here we consider the case of signalling between isolated cell pairs, and find that the bifurcation properties of a standard mathematical model of lateral inhibition can lead to stable symmetric signalling states. We apply this model to the adult intestinal stem cell (ISC) of Drosophila, whose fate is stochastic but dependent on the Notch/Delta pathway. We observe a correlation between signalling state in cell pairs and their contact area. We interpret this behaviour in terms of the properties of our model in the presence of population variability in signalling thresholds. Our results suggest that the dynamics of Notch/Delta signalling can contribute ...
Cis-activation in the Notch signaling pathway
eLife
The Notch signaling pathway consists of transmembrane ligands and receptors that can interact both within the same cell (cis) and across cell boundaries (trans). Previous work has shown that cis-interactions act to inhibit productive signaling. Here, by analyzing Notch activation in single cells while controlling cell density and ligand expression level, we show that cis-ligands can also activate Notch receptors. This cis-activation process resembles trans-activation in its ligand level dependence, susceptibility to cis-inhibition, and sensitivity to Fringe modification. Cis-activation occurred for multiple ligand-receptor pairs, in diverse cell types, and affected survival in neural stem cells. Finally, mathematical modeling shows how cis-activation could potentially expand the capabilities of Notch signaling, for example enabling ‘negative’ (repressive) signaling. These results establish cis-activation as an additional mode of signaling in the Notch pathway, and should contribute ...
The intracellular domain of Notch ligand Delta1 induces cell growth arrest
FEBS Letters, 2005
Notch signaling involves proteolytic cleavage of the transmembrane Notch receptor after binding to its transmembrane ligands, Delta or Jagged; and the resultant soluble intracellular domain of Notch stimulates a cascade of transcriptional events. The Delta1 ligand also undergoes proteolytic cleavage upon Notch binding, resulting in the production of a free intracellular domain. We demonstrate that the expression of the intracellular domain of Delta1 results in a non-proliferating senescent-like cell phenotype which is dependent on the expression of the cell cycle inhibitor, p21, and is abolished by coexpression of constitutively active Notch1. These data suggest a new intracellular role for Delta1.
Molecules and Cells, 2011
Notch signaling involves the proteolytic cleavage of the transmembrane Notch receptor after binding to its transmembrane ligands. The Delta-like ligand 1 also undergoes proteolytic cleavage upon Notch binding, resulting in the production of a free intracellular domain. In this study, we have demonstrated that the Delta-like 1 intracellular domain (Dll1-IC) specifically binds to Notch1-IC in the nucleus, thereby disrupting the association of the Notch1-IC-RBP-Jk-MAM transcription activator complex. Additionally, the Notch1-mediated blockage of the induction of MyoD is abolished by the co-expression of Dll1-IC. Collectively, our results show that Dll1-IC functions as a negative regulator in Notch signaling via the disruption of the Notch1-IC-RBP-Jk complex. Plasmid constructs The mouse Notch1-IC and mouse Dll1 deletion mutants con
Delta activity independent of its activity as a ligand of Notch
BMC developmental biology, 2005
Delta, Notch, and Scabrous often function together to make different cell types and refine tissue patterns during Drosophila development. Delta is known as the ligand that triggers Notch receptor activity. Scabrous is known to bind Notch and promote Notch activity in response to Delta. It is not known if Scabrous binds Delta or Delta has activity other than its activity as a ligand of Notch. It is very difficult to clearly determine this binding or activity in vivo as all Notch, Delta, and Scabrous activities are required simultaneously or successively in an inter-dependent manner. Using Drosophila cultured cells we show that the full length Delta promotes accumulation of Daughterless protein, fringe RNA, and pangolin RNA in the absence of Scabrous or Notch. Scabrous binds Delta and suppresses this activity even though it increases the level of the Delta intracellular domain. We also show that Scabrous can promote Notch receptor activity, in the absence of Delta. Delta has activity ...
The Notch signaling pathway: Molecular basis of cell context dependency
European Journal of Cell Biology, 2011
Notch receptor signaling controls cell-fate specification, self-renewal, differentiation, proliferation and apoptosis throughout development and regeneration in all animal species studied to date. Its dysfunction causes several developmental defects and diseases in the adult. A key feature of Notch signaling is its remarkable cell-context dependency. In this review, we summarize the influences of the cellular context that regulate Notch activity and propose a model how the interplay between the cell-intrinsically established chromatin state and the cell-extrinsic signals that modify chromatin may select for Notch target accessibility and activation in different cellular contexts.