During pancreatic development in mammals and zebrafish, Notch-responsive cells (NRCs) give rise to endocrine cells, but how does Notch signalling regulate the proliferation and differentiation of pancreatic progenitors at the single-cell level? On , Nikolay Ninov and co-workers use live imaging and a novel transgenic reporter system that allows the dynamic assessment of Notch signalling to answer this question in zebrafish larvae. The researchers show that zebrafish NRCs exhibit different levels of Notch signalling that, in turn, regulate distinct cellular outcomes. Specifically, high levels of Notch signalling induce quiescence, lower levels promote progenitor amplification, and sustained downregulation of Notch signalling triggers a multistep process that includes cell-cycle entry and amplification followed by endocrine differentiation. Importantly, the researchers show that progenitor amplification and differentiation can be uncoupled by modulating the duration and/or level of Notch signalling downregulation. Thus, different levels of Notch signalling drive distinct behaviours in pancreatic endocrine precursors, a finding that could inform the development of regenerative therapies for type 1 diabetes.
