Neural fate decisions mediated by <i>trans</i>-activation and <i>cis</i>-inhibition in Notch signaling

Wang, Ruiqi; Kaihui, Liu; Chen, Luonan; Aihara, Kazuyuki

doi:10.1093/bioinformatics/btr551

Cited by 43 publications

(46 citation statements)

References 29 publications

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“…Our results confirmed that Notch-Delta alone allows only two states: Sender (S) or Receiver (R), which is consistent with previous studies (6,13,14,17). Our key findings are that due to the Delta-Jagged asymmetry, the Notch signaling through both Delta and Jagged gives rise to a hybrid Sender/Receiver (S/R) state in addition to Sender and Receiver states.…”

Section: Discussionsupporting

confidence: 92%

“…Whereas Notch-Delta signaling has been extensively studied both theoretically and experimentally (6,(13)(14)(15)(16)(17) and is well understood, the role of Jagged in the Notch-Delta-Jagged signaling is still elusive. Here, we introduced a specially designed theoretical framework to study Notch signaling through both Delta and Jagged which incorporates the effect of the asymmetries between these two key ligands.…”

Section: Discussionmentioning

confidence: 99%

“…Many experimental and theoretical research efforts have been directed toward understanding the Notch-Delta-dependent cellfate determination (6,(13)(14)(15)(16)(17). In contrast, the role of NotchJagged signaling has gained limited research attention despite the recognized role of Jagged in tumorigenesis.…”

mentioning

confidence: 99%

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

Boareto

Jolly

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

139

226

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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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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

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

Boareto

Jolly

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

139

226

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“…In mathematical models, critical thresholds for such transitions correspond to bifurcations [6]. Typical bifurcations are those that mark the transition from one stable equilibrium to another one through a saddle-node or a pitchfork bifurcation [7] or the transition from an oscillatory attractor to a stable equilibrium through a Hopf bifurcation [8].…”

Section: Introductionmentioning

confidence: 99%

Bifurcation-based approach reveals synergism and optimal combinatorial perturbation

Liu

et al. 2016

J Biol Phys

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Cells accomplish the process of fate decisions and form terminal lineages through a series of binary choices in which cells switch stable states from one branch to another as the interacting strengths of regulatory factors continuously vary. Various combinatorial effects may occur because almost all regulatory processes are managed in a combinatorial fashion. Combinatorial regulation is crucial for cell fate decisions because it may effectively integrate many different signaling pathways to meet the higher regulation demand during cell development. However, whether the contribution of combinatorial regulation to the state transition is better than that of a single one and if so, what the optimal combination strategy is, seem to be significant issue from the point of view of both biology and mathematics. Using the approaches of combinatorial perturbations and bifurcation analysis, we provide a general framework for the quantitative analysis of synergism in molecular networks. Different from the known methods, the bifurcation-based approach depends only on stable state responses to stimuli because the state transition induced by combinatorial perturbations occurs between stable states. More importantly, an optimal combinatorial perturbation strategy can be determined by investigating the relationship between the bifurcation curve of a synergistic perturbation pair and the level set of a specific objective function. The approach is applied to two models, i.e., a theoretical multistable decision model and a biologically realistic CREB model, to show its validity, although the approach holds for a general class of biological systems.

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“…These two levels of asymmetry in Notch-Delta vs. Notch-Jagged signaling call for elucidating their different operating principles. Much experimental and theoretical research efforts have been directed towards understanding the Notch-Delta-dependent cell fate determination [10,20,21,22,23,24]. In contrast, the role of Notch-Jagged signaling has gained limited research attention despite its crucial role during embryonic development, and promoting tumor progression in multiple ways.…”

Section: Introductionmentioning

confidence: 99%

Tópicos em sinalização celular e bioinformática: Princípios de funcionamento do circuito de sinalização Notch e aprendizagem supervisionada variacional de relevância

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Neural fate decisions mediated by trans-activation and cis-inhibition in Notch signaling

Cited by 43 publications

References 29 publications

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

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

Bifurcation-based approach reveals synergism and optimal combinatorial perturbation

Tópicos em sinalização celular e bioinformática: Princípios de funcionamento do circuito de sinalização Notch e aprendizagem supervisionada variacional de relevância

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