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.
Highlights
In the Drosophila notum, Notch-mediated lateral inhibition drives the emergence of a patterned array of microchaete, or small mechanosensory bristles, ∼8-18 h after pupariation (AP) at 25°C (Fig. 1A; Movie 1) (Simpson et al, 1999; Furman and Bukharina, 2008; Cohen et al, 2010)
By simultaneously following cell division and patterning in this tissue, we find that local patterns of division timing correlate with proximity to sensory organ precursor cell (SOP) (Fig. 1B-D)
Relative timing of SOP cell and epithelial cells (ECs) division is crucial for bristle patterning To examine the consequences of the observed coupling between Notch signalling and cell cycle progression on tissue patterning, we developed a mathematical model of lateral inhibition (Cohen et al, 2010; Sprinzak et al, 2010)
Summary
In the Drosophila notum, Notch-mediated lateral inhibition drives the emergence of a patterned array of microchaete, or small mechanosensory bristles, ∼8-18 h after pupariation (AP) at 25°C (Fig. 1A; Movie 1) (Simpson et al, 1999; Furman and Bukharina, 2008; Cohen et al, 2010). Together with the ablation data, this shows that NsfGFP signal in ECs is dependent upon Delta-expressing SOPs. we examined the effects of disrupting Notch signalling on cell division timing by overexpressing DeltaDN in SOPs (Fig. 2I) or using RNAi against Suppressor of Hairless [Su(H)], an essential component of Notch-targeted gene expression (Lehman et al, 1999; Furriols and Bray, 2001) across the tissue.
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