Notch signaling regulates neural stem cell quiescence entry and exit in Drosophila

Abstract

Stem cells enter and exit quiescence as part of normal developmental programs and to maintain tissue homeostasis in adulthood. While it is clear that stem cell intrinsic and extrinsic cues, local and systemic, regulate quiescence, it remains unclear whether intrinsic and extrinsic cues coordinate to control quiescence and how cue coordination is achieved. Here, we report that Notch signaling coordinates neuroblast intrinsic temporal programs with extrinsic nutrient cues to regulate quiescence in Drosophila. When Notch activity is reduced, quiescence is delayed or altogether bypassed, with some neuroblasts dividing continuously during the embryonic to larval transition. During embryogenesis before quiescence, neuroblasts express Notch and the Notch ligand, Delta. After division, Delta is partitioned to adjacent GMC daughters where it transactivates Notch in neuroblasts. Over time in response to intrinsic temporal cues and increasing numbers of Delta-expressing daughters, neuroblast Notch activity increases leading to cell cycle exit and consequently, attenuation of Notch pathway activity. Quiescent neuroblasts have low to no active Notch, which is required for exit from quiescence in response to nutrient cues. Thus, Notch signaling coordinates proliferation versus quiescence decisions.

Multiomic Analysis of Adult Diapause inDrosophila melanogasterIdentifies Hallmarks of Cellular Quiescence

“…Hippo signaling coordinates the restriction of growth during development and the maintenance of stem cell quiescence in Drosophila (Halder & Johnson, 2011; Staley & Irvine, 2012; Ding et al, 2016; Jin et al, 2013). As previously addressed, Notch signaling also plays an important role in maintaining Drosophila stem cell quiescence (Bjornson et al, 2013; Bernard et al, 2010; Sood et al, 2022; Anant et al, 1998). Its reappearance in our RNA-seq reaffirms the importance of this pathway for diapause, well as the robustness of our data.…”

“…5C). Both pathways are essential to the maintenance of stem cell identity and the induction of cellular quiescence, depending on environmentally and developmentally timed cues (Dey et al, 2016; Firth et al, 2010; Sood et al, 2022). Interestingly, Notch signaling has also been shown control differentiation through its effects on fatty acid metabolism (Garcés et al, 1997; Jabs et al, 2018).…”

“…However, quiescence also entails upregulation of genes responsible for preventing differentiation, maintaining cellular homeostasis, and the transduction of mitogenic signals, such that the cell remains primed for rapid return to the cell cycle. Positive regulation of the Notch (N) and Hippo (hpo) signaling pathways is crucial to maintaining undifferentiated cell identity in quiescence (van Velthoven & Rando, 2019; Sood et al, 2022; Bjornson et al, 2012; Ding et al, 2016). The prevention of damage accumulation is another necessary function in quiescence insofar as the cell must preserve its genomic integrity for future replication.…”

Delta-dependent Notch activation closes the early neuroblast temporal program to promote lineage progression and neurogenesis termination inDrosophila

“…We also reported that Notch activity becomes attenuated in quiescent CB NBs because CB NBs are no longer dividing and producing Delta-expressing GMC daughters for Notch pathway transactivation. Moreover, low Notch is necessary for CB NBs to reactivate from quiescence in response to dietary nutrients (Sood et al, 2022).…”

“…Cleaved Notch ICD (intracellular domain) relocates to the nucleus where it binds to Suppressor of Hairless [Su(H)] and Mastermind to regulate gene expression (Rebay et al, 1991; Fortini and Artavanis-Tsakonas, 1994; Pan and Rubin, 1997; Strooper et al, 1999; Mumm et al, 2000; Kitagawa et al, 2001; Kopan and Ilagan, 2009). We recently reported that Notch signaling regulates CB NB quiescence during the embryonic to larval transition (Sood et al, 2022). When Notch is knocked down, some CB NBs continue dividing during this transition.…”