title: Different levels of Notch signaling regulate quiescence, renewal and differentiation in pancreatic endocrine progenitors.
abstract: 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.
authors.affiliation: Department of Biochemistry and Biophysics, Programs in Developmental and Stem Cell Biology, Genetics and Human Genetics, Diabetes Center, and Liver Center, University of California, San Francisco, San Francisco, CA 94158, USA. nikolay.ninov@ucsf.edu
authors.forename: Nikolay
authors.initials: N
authors.lastname: Ninov
authors.forename: Maxim
authors.initials: M
authors.lastname: Borius
authors.forename: Didier Y R
authors.initials: DY
authors.lastname: Stainier
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D002454:Cell Differentiation / Q000502:physiology*; D049109:Cell Proliferation; D005455:Fluorescent Antibody Technique; D007515:Islets of Langerhans / Q000166:cytology*; D007814:Larva / Q000378:metabolism / Q000502:physiology; D051880:Receptors, Notch / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D013234:Stem Cells / Q000502:physiology*; D015027:Zebrafish / Q000254:growth & development* / Q000378:metabolism
chemical_list: D051880:Receptors, Notch