Coordinated control of Notch-Delta signalling and cell cycle progression drives lateral inhibition mediated tissue patterning

Abstract

Coordinating cell differentiation with cell growth and division is crucial for the successful development, homeostasis and regeneration of multicellular tissues. Here, we use bristle patterning in the fly notum as a model system to explore the regulatory and functional coupling of cell cycle progression and cell fate decision-making. The pattern of bristles and intervening epithelial cells (ECs) becomes established through Notch-mediated lateral inhibition during G2 phase of the cell cycle, as neighbouring cells physically interact with each other via lateral contacts and/or basal protrusions. Since Notch signalling controls cell division timing downstream of Cdc25, ECs in lateral contact with a Delta-expressing cell experience higher levels of Notch signalling and divide first, followed by more distant neighbours, and lastly Delta-expressing cells. Conversely, mitotic entry and cell division makes ECs refractory to lateral inhibition signalling, fixing their fate. Using a combination of experiments and computational modelling, we show that this reciprocal relationship between Notch signalling and cell cycle progression acts like a developmental clock, providing a delimited window of time during which cells decide their fate, ensuring efficient and orderly bristle patterning.

The Canonical Notch Signaling Pathway: Structural and Biochemical Insights into Shape, Sugar, and Force

“…Recent evidence suggests that Notch signals can be transduced through filopodial contacts (Cohen et al, 2010; Hunter et al, 2016). Since endocytosis does not occur in filopodia, a potential pulling force generator could be the active transport mediated by molecular motors (Kerber and Cheney, 2011).…”

“…It was also suggested that signaling through filopodia allows for an extended range by which prospective SOPs can inhibit neighboring cells, thus allowing for larger spacing between SOP cells. More recent work by Hunter et al suggests that differences in the level of signaling between SOP and its direct (cells that share apical contact) and indirect neighbors (cells in contact through filopodia) are important for ordered and timely progression of SOP patterning (Hunter et al, 2016). However, a recent paper by Troost et al (Troost et al, 2015) provides evidence against the filopodial model of SOP patterning, showing that only cells adjacent to the SOP receive inhibitory Notch signals.…”

Cycling through developmental decisions: how cell cycle dynamics control pluripotency, differentiation and reprogramming

“…During bristle patterning in Drosophila, Notch signaling controls transition through late stages of the cell cycle such that cells with elevated Notch signaling divide first and those with lower signaling extend their G2 phase and delay division (Hunter et al, 2016). This G2-phase transition time is crucial for determining the decision of sensory organ precursor cells to progress to a microchaete fate or a neural fate.…”

A new mechanism for spatial pattern formation via lateral and protrusion-mediated lateral signalling

“…Here, short junctional contacts and long-range protrusion-mediated contacts between different cell types lead to the mutual attraction or repulsion among cells that self-organize into stripes [2,10]. The regularly spaced bristle precursor cells in the Drosophila notum also rely on the combination of direct and protrusion-mediated signals [1,11]. In this system, cells expressing high levels of the Delta ligand inhibit the expression of Delta, via Notch activation, in other cells within their reach.…”

“…In this system, cells expressing high levels of the Delta ligand inhibit the expression of Delta, via Notch activation, in other cells within their reach. The result is a regularly spaced pattern of individual cells expressing high levels of Delta in a sea of cells expressing low levels of Delta (figure 1 a,b ) [1,11]. In this way, contact-mediated signalling can lead to the generation of periodic patterns in an initially homogeneous tissue without the requirement for cell motility or a pre-pattern.…”