Mechanisms of stem cell preservation and lifespan extension in Drosophila

在包括人类在内的许多物种中，衰老的众多后果之一是 生育率下降，特别是女性生育率下降。耐人寻味的是，有些物种可以 在特定的环境条件下，生育的时间比没有生育的时间更长。 例如，不同种类的果蝇进入一种被称为成年生殖的状态 当它们经历低温和较短的白天时，它们会滞育。在这些下面 在条件允许的情况下，他们可以在保持生育能力的同时将寿命延长一倍。以前的工作有 涉及几个基因对成虫生殖滞育的正或负调节 在果蝇身上。例如，胰岛素途径负向调节滞育， 提出了一种与新陈代谢、生育、 以及其他物种的寿命，包括线虫、老鼠和人类。然而，我们的 对滞育的机械理解是极其有限的，以及育性如何 保存完好是未知的。我们已经利用了果蝇强大的遗传工具 开展全基因组滞育关联研究。这种方法似乎是 非常成功，因为从分析中发现了为数不多的已知基因，例如 胰岛素受体。此外，这张屏幕揭示了最丰富的网络 与滞育相关的基因包括那些参与神经元发育和 雌性生殖。神经元发育基因是惊人的，但事实并非如此 以前与滞育有关，因此提供了新的分子和 细胞洞察力。在这里，我们建议：1)确定控制特定步骤的基因 滞育程序，如进入、维持、退出、保持繁殖力和 寿命；2)测试在发育过程中是否需要滞育基因 滞育的动物，或成年期特有的功能；以及3)调查 育种系干细胞滞育保存的分子机制。我们 预计，就像对线虫达尔形成的研究照亮了一般 调节动物新陈代谢、生长、生殖和衰老的途径 从蠕虫到人类，对果蝇滞育的研究提供了令人兴奋的潜力 揭示干细胞保存、维持生育能力、 和延年益寿。

Across many species, including humans, one of the many consequences of aging is a reduction in fertility, particularly female fertility. Intriguingly some species can preserve fertility for longer than they otherwise would, under specific environmental conditions. For example, various species of Drosophila enter a state called adult reproductive diapause when they experience low temperatures and short day length. Under these conditions they can double their lifespan while maintaining fertility. Previous work has implicated a few genes in positive or negative regulation of adult reproductive diapause in Drosophila. For example, the insulin pathway negatively regulates diapause, suggesting mechanisms that are conserved with the regulation of metabolism, fertility, and lifespan in other species including C. elegans, mice, and humans. However, our mechanistic understanding of diapause is extremely limited, and how fertility is preserved is unknown. We have taken advantage of powerful genetic tools in Drosophila to carry out a genome-wide association study of diapause. This approach appears to be highly successful, as the few known genes emerged from the analysis, such as the insulin receptor. In addition, this screen revealed that the most highly enriched networks of genes associated with diapause include those involved in neuronal development and female reproduction. The neuronal development genes are striking, as they have not previously been associated with diapause and thus offer to provide new molecular and cellular insights. Here we propose to: 1) identify the genes controlling specific steps in the diapause program such as entry, maintenance, exit, preservation of fecundity, and lifespan; 2) test whether diapause genes are required during development to prepare the animals for diapause, or function specifically in adulthood; and 3) investigate the molecular mechanisms of germline stem cell preservation during diapause. We anticipate that just as studies of C. elegans dauer formation illuminated general pathways regulating metabolism, growth, reproduction and aging in animals ranging from worms to humans, studies of Drosophila diapause offer the exciting potential to uncover novel and general mechanisms of stem cell preservation, fertility maintenance, and lifespan extension.