Diversity of fate outcomes in cell pairs under lateral inhibition

Abstract

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.

A genetic framework controlling the differentiation of intestinal stem cells during regeneration in Drosophila

“…Previous studies have also shown that progenitor nests are outlined by E-Cadherin/β-Catenin complexes [23, 48], yet it was not known whether different degrees of progenitor contact are associated with their ISC versus EB fate. Consistent with our results, recent modeling analyses suggested a positive correlation between the contact area of progenitor pairs and the activation of Notch signaling [53, 54]. Thus, it seems that an increase in the contact area between intestinal progenitors is a hallmark of progenitors that are undergoing accelerated differentiation towards ECs.…”

Spatial patterning of the Notch ligand Dll4 controls endothelial sprouting in vitro

“…This unidirectional sprouting is a direct result of the restrictions set by the patterned Dll4 beads. Recent data on Notch dose sensitivity in cell fate determination 28 and the finding that cell-cell contact area influences the Notch pathway’s signalling strength 29 , 30 support our idea that the controlled dose and location of the Dll4 ligand is responsible of forcing the endothelial phenotype. Additionally, lateral inhibition has previously been pointed out to be a possible tool for the control over cell to cell patterning 31 .…”

Cell Polarity and Notch Signaling: Linked by the E3 Ubiquitin Ligase Neuralized?

“…Indeed, cells of the basilar papilla that are selected by low Notch activity to become hair cells have a small apical perimeter relative to their neighbors in developing chicks . Similarly, in the fly gut, the contact area between the two daughters produced by the division of intestinal stem cells correlate with the level of Notch signaling, hence cell fate . Moreover, extended cell–cell contact between daughter cells appears to promote Notch‐dependent differentiation of progenitor cells during gut regeneration .…”

“…In various developmental contexts, proper cell fate decisions depend on Notch activity levels . At the level of receptor activation, signaling strength may be approximated by the number of receptors cleaved per time unit.…”