Department of Biology, University of Virginia, Charlottesville, VA 22904, USA.
Development. 2022 Feb 15;149(4). doi: 10.1242/dev.200275. Epub 2022 Feb 18.
Stem cells enter and exit quiescence as part of normal developmental programs and to maintain tissue homeostasis in adulthood. Although 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.
干细胞作为正常发育程序的一部分进入和退出静息状态，以维持成年期组织的稳态。尽管很明显，干细胞内在和外在的线索，局部和全身的，调节静息状态，但仍然不清楚内在和外在的线索是否协调来控制静息状态，以及如何协调线索的协调。在这里，我们报告说，Notch 信号协调果蝇神经母细胞内在的时间程序与外在的营养线索，以调节静息状态。当 Notch 活性降低时，静息状态被延迟或完全绕过，一些神经母细胞在胚胎到幼虫的过渡期间连续分裂。在静息前的胚胎发生过程中，神经母细胞表达 Notch 和 Notch 配体 Delta。分裂后，Delta 被分配到相邻的 GMC 女儿那里，它在神经母细胞中转录激活 Notch。随着时间的推移，响应内在的时间线索和越来越多表达 Delta 的女儿，神经母细胞 Notch 活性增加，导致细胞周期退出，从而减弱 Notch 途径活性。静息的神经母细胞具有低至无活性的 Notch，这是对营养线索响应退出静息状态所必需的。因此，Notch 信号协调增殖与静息状态决策。
