View Program - 63rd Annual Drosophila Research Conference

In most metazoans, neural stem cells (NSCs) proliferate throughout development and then terminate their cell divisions prior to developmental completion. This ensures the formation of an adult neural circuit system that is functional and stable. To better understand the cellular and molecular mechanisms that regulate termination of NSC cell divisions and neurogenesis during development, we carried out a large scale GAL4/UAS-RNAi screen in Drosophila. From this screen, we identified the Notch receptor and its ligand Delta. When Notch or Delta are knocked down, neuroblast divisions in the central brain region continue into adulthood, whereas when Notch is constitutively activated, neuroblast divisions terminate prematurely. We found that defects in Notch-mediated timing of termination are due to defects in neuroblast temporal patterning. When either Notch or Delta are knocked down, expression of the early temporal factor Imp (IgF-II mRNA binding protein) is maintained longer compared to controls, concomitant with delayed expression of the late acting temporal factor, Syp (Syncrip). This leads to an increase in the number of Imp and Syp double positive neuroblasts, or neuroblasts with mixed temporal identity and reduced expression of the even later temporal factor, E93 (Eip93F). However, surprisingly, when we knocked down Imp and Notch signaling or overexpressed Syp and knocked down Notch signaling, the central brain neuroblasts still persisted into adulthood. This suggests that Delta/Notch cell signaling may regulate both temporal patterning and neuroblast cell cycle exit. To better understand whether Notch regulates neuroblast cell cycle exit independent of Imp/Syp temporal patterning, we assayed neuroblast quiescence during the embryonic to larval transition. When Notch is knocked down, some neuroblasts fail to enter quiescence and continue proliferating during the embryonic to larval transition. We conclude that the evolutionarily conserved Delta/Notch cell-cell signaling pathway regulates the Imp to Syp temporal transition and regulates neuroblast cell cycle exit. While Notch signaling is well known for its role in regulating binary cell fate decisions, it is becoming more apparent that Notch signaling also plays important roles in binary temporal decisions, in this case, early versus late.

Delta/Notch signaling inhibits expression of the early temporal factor Imp to promote termination of neurogenesis during development