Ninov, N., Borius, M., and Stainier, D.Y. (2012) Different levels of Notch signaling regulate quiescence, renewal and differentiation in pancreatic endocrine progenitors. Development (Cambridge, England). 139(9):1557-1567.
Genetic studies have implicated Notch signaling in the maintenance of pancreatic progenitors. However, how Notch signaling
regulates the quiescent, proliferative or differentiation behaviors of pancreatic progenitors at the single-cell level remains
unclear. Here, using single-cell genetic analyses and a new transgenic system that allows dynamic assessment of Notch signaling,
we address how discrete levels of Notch signaling regulate the behavior of endocrine progenitors in the zebrafish intrapancreatic
duct. We find that these progenitors experience different levels of Notch signaling, which in turn regulate distinct cellular
outcomes. High levels of Notch signaling induce quiescence, whereas lower levels promote progenitor amplification. The sustained
downregulation of Notch signaling triggers a multistep process that includes cell cycle entry and progenitor amplification
prior to endocrine differentiation. Importantly, progenitor amplification and differentiation can be uncoupled by modulating
the duration and/or extent of Notch signaling downregulation, indicating that these processes are triggered by distinct levels
of Notch signaling. These data show that different levels of Notch signaling drive distinct behaviors in a progenitor population.