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

Boareto, Marcelo; Jolly, Mohit Kumar; Lu, Mingyang; Onuchic, José N.; Clementi, Cecilia; Ben‐Jacob, Eshel

doi:10.1073/pnas.1416287112

Cited by 131 publications

(231 citation statements)

References 63 publications

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“…However, to allow accommodating phenomenology that departs from the classical fine-grained all-or-none patterns, expansions of this model have required the introduction of additional genetic components (e.g. an extra ligand; Boareto et al, 2015) or noise components (de Back et al, 2013). By contrast, here we have left intact the general dynamics of the minimal model and simply introduced a degree of variability in the sensitivity of each cell pair to signal transduction.…”

Section: Discussionmentioning

confidence: 99%

Diversity of fate outcomes in cell pairs under lateral inhibition

et al. 2017

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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, the fate of which 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 contact areas, which affects the effective signalling threshold of individual cells. Our results suggest that the dynamics of Notch/Delta signalling can contribute to explain stochasticity in stem cell fate decisions, and that the standard model for lateral inhibition can account for a wider range of developmental outcomes than previously considered.

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Section: Discussionmentioning

confidence: 99%

Diversity of fate outcomes in cell pairs under lateral inhibition

et al. 2017

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“…An understanding of how qualitative and quantitative aspects of Notch signaling govern gene expression output remains elusive (see Boareto et al, 2015;Shaya and Sprinzak, 2011;Sprinzak et al, 2010). Notch1 and Notch2 have been shown to have different contributions in certain cellular, developmental and disease contexts, while having equal contributions in others.…”

Section: Discussionmentioning

confidence: 99%

The intracellular domains of Notch1 and 2 are functionally equivalent during development and carcinogenesis

et al. 2015

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Although Notch1 and Notch2 are closely related paralogs and function through the same canonical signaling pathway, they contribute to different outcomes in some cell and disease contexts. To understand the basis for these differences, we examined in detail mice in which the Notch intracellular domains (N1ICD and N2ICD) were swapped. Our data indicate that strength (defined here as the ultimate number of intracellular domain molecules reaching the nucleus, integrating ligand-mediated release and nuclear translocation) and duration (half-life of NICD-RBPjk-MAML-DNA complexes, integrating cooperativity and stability dependent on shared sequence elements) are the factors that underlie many of the differences between Notch1 and Notch2 in all the contexts we examined, including T-cell development, skin differentiation and carcinogenesis, the inner ear, the lung and the retina. We were able to show that phenotypes in the heart, endothelium, and marginal zone B cells are attributed to haploinsufficiency but not to intracellular domain composition. Tissue-specific differences in NICD stability were most likely caused by alternative scissile bond choices by tissue-specific γ-secretase complexes following the intracellular domain swap. Reinterpretation of clinical findings based on our analyses suggests that differences in outcome segregating with Notch1 or Notch2 are likely to reflect outcomes dependent on the overall strength of Notch signals.

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“…However, unlike other contexts where Notch-Delta (N-D) signaling leads to salt-and-pepper patterns, i.e., pattern of alternate fates with a wavelength of one cell, in angiogenesis, the two tip cells are usually separated by a few stalk cells, all of which have low Delta but high Jagged (Jag1) levels (14). Thus, NotchJagged (N-J) signaling that regulates lateral induction (6,8,15), i.e., propagation of the same cell fate in adjacent cells, might decide the distance between two tip cells (Fig. 1B).…”

Section: Significancementioning

confidence: 99%

Jagged mediates differences in normal and tumor angiogenesis by affecting tip-stalk fate decision

Boareto

Jolly

Ben‐Jacob

et al. 2015

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

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Angiogenesis is critical during development, wound repair, and cancer progression. During angiogenesis, some endothelial cells adopt a tip phenotype to lead the formation of new branching vessels; the trailing stalk cells proliferate to develop the vessel. Notch and VEGF signaling mediate the selection of these tip endothelial cells. However, how Jagged, a Notch ligand that is overexpressed in cancer, affects angiogenesis remains elusive. Here, by developing a theoretical framework for Notch-Delta-Jagged-VEGF signaling, we found that higher production levels of Jagged destabilizes the tip and stalk cell fates and can give rise to a hybrid tip/stalk phenotype that leads to poorly perfused and chaotic angiogenesis, which is a hallmark of cancer. Consistently, the signaling interactions that restrict Notch-Jagged signaling, such as Fringe, cis-inhibition, and increased production of Delta, stabilize tip and stalk fates and limit the existence of hybrid tip/stalk phenotype. Our results underline how overexpression of Jagged can transform physiological angiogenesis into pathological one.

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

Cited by 131 publications

References 63 publications

Diversity of fate outcomes in cell pairs under lateral inhibition

Diversity of fate outcomes in cell pairs under lateral inhibition

The intracellular domains of Notch1 and 2 are functionally equivalent during development and carcinogenesis

Jagged mediates differences in normal and tumor angiogenesis by affecting tip-stalk fate decision

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