Department of Physiological Chemistry, Graduate School of Pharmaceutical Sciences, University of Tokyo , 113-0033 , Japan ; Department of Genetics, Cell Biology and Development, University of Minnesota , MN 55455 , USA.
Biol Open. 2012 Oct 15;1(10):929-36. doi: 10.1242/bio.2012836. Epub 2012 Aug 2.
Mechanisms controlling development, growth, and metabolism are coordinated in response to changes in environmental conditions, enhancing the likelihood of survival to reproductive maturity. Much remains to be learned about the molecular basis underlying environmental influences on these processes. C. elegans larvae enter a developmentally dormant state called L1 diapause when hatched into nutrient-poor conditions. The nematode pten homologue daf-18 is essential for maintenance of survival and germline stem cell quiescence during this period (Fukuyama et al., 2006; Sigmond et al., 2008), but the details of the signaling network(s) in which it functions remain to be elucidated. Here, we report that animals lacking both aak-1 and aak-2, which encode the two catalytic α subunits of AMP-activated protein kinase (AMPK), show reduced viability and failure to maintain mitotic quiescence in germline stem cells during L1 diapause. Furthermore, failure to arrest germline proliferation has a long term consequence; aak double mutants that have experienced L1 diapause develop into sterile adults when returned to food, whereas their continuously fed siblings are fertile. Both aak and daf-18 appear to maintain germline quiescence by inhibiting activity of the common downstream target, TORC1 (TOR Complex 1). In contrast, rescue of the lethality phenotype indicates that aak-2 acts not only in the intestine, as does daf-18, but also in neurons, likely promoting survival by preventing energy deprivation during L1 diapause. These results not only provide evidence that AMPK contributes to survival during L1 diapause in a manner distinct from that by which it controls dauer diapause, but they also suggest that AMPK suppresses TORC1 activity to maintain stem cell quiescence.
控制发育、生长和代谢的机制在环境条件变化时协调一致，提高了生存到生殖成熟的可能性。关于环境对这些过程的影响的分子基础，还有很多需要了解。当 C. elegans 幼虫孵化到营养贫乏的条件下时，它们会进入一种发育休眠状态，称为 L1 休眠。线虫 pten 同源物 daf-18 在这段时间内对维持生存和生殖干细胞静止至关重要（Fukuyama 等人，2006 年；Sigmond 等人，2008 年），但其功能的信号转导网络的细节仍有待阐明。在这里，我们报告说，缺乏编码 AMP 激活蛋白激酶 (AMPK) 的两个催化α亚基的 aak-1 和 aak-2 的动物表现出存活率降低和在 L1 休眠期间生殖干细胞中无法维持有丝分裂静止。此外，生殖细胞增殖的失败具有长期后果；经历过 L1 休眠的 aak 双突变体在返回食物时发育成不育成虫，而它们持续喂食的兄弟姐妹则是可育的。aak 和 daf-18 似乎通过抑制共同下游靶标 TORC1（TOR 复合物 1）的活性来维持生殖细胞静止。相比之下，拯救致死表型表明 aak-2 的作用不仅与 daf-18 一样在肠中，而且还在神经元中，可能通过在 L1 休眠期间防止能量剥夺来促进生存。这些结果不仅提供了证据表明 AMPK 通过不同于控制 dauer 休眠的方式在 L1 休眠期间有助于生存，而且还表明 AMPK 抑制 TORC1 活性以维持干细胞静止。
