Nutrient-Dependent Endocycling in Steroidogenic Tissue Dictates Timing of Metamorphosis in Drosophila melanogaster.
Nutrient-Dependent Endocycling in Steroidogenic Tissue Dictates Timing of Metamorphosis in Drosophila melanogaster.
复制标题
DOI：
10.1371/journal.pgen.1006583
复制
发表时间：
2017-01
期刊：
影响因子：
4.5
通讯作者：
Yamanaka N
中科院分区：
文献类型：
--
作者：
Ohhara Y;Kobayashi S;Yamanaka N
许多动物在幼年发育过程中都有一个内在的生长检查点，之后做出不可逆转的决定来上调类固醇生成，从而引发幼年向成年的变质转变。然而，这种关键发育决定背后的分子过程仍然不清楚。在这里，我们表明，类固醇生成细胞中营养依赖性内循环为果蝇变态的不可逆激活提供了必要的机制。前胸腺 (PG) 细胞内周期的进展与生长检查点紧密结合，PG 细胞内周期的阻断会因类固醇激素蜕皮激素生物合成的减少而导致幼虫发育停滞。此外，在检查点期间抑制 PG 中雷帕霉素 (TOR) 的营养传感器靶点会导致内周期抑制和发育停滞，这可以通过 Cyclin E 诱导额外几轮内循环来挽救。我们提出，类固醇生成组织中 TOR 介导的细胞周期检查点为生殖成熟提供了系统生长检查点。动物性成熟的开始是一个不可逆转的时刻。一旦做出了这一改变生命的决定，类固醇生成的上调就会导致人类和昆虫从幼年到成年的不可逆转的转变。虽然有助于这一决策过程的营养信号已得到充分研究，但最终决定其精确时间的分子事件仍然是一个谜。我们在此报告，类固醇生成细胞中营养依赖性内复制（即不进行细胞分裂的基因组 DNA 复制）充当内在计时器，由此多倍体程度决定了果蝇生殖成熟（即变态）的时间。因此，内复制的累积性和不可逆性提供了不可逆决策过程背后的内在分子机制，该机制可以被广泛用作基本的发育计时机制。
Many animals have an intrinsic growth checkpoint during juvenile development, after which an irreversible decision is made to upregulate steroidogenesis, triggering the metamorphic juvenile-to-adult transition. However, a molecular process underlying such a critical developmental decision remains obscure. Here we show that nutrient-dependent endocycling in steroidogenic cells provides the machinery necessary for irreversible activation of metamorphosis in Drosophila melanogaster. Endocycle progression in cells of the prothoracic gland (PG) is tightly coupled with the growth checkpoint, and block of endocycle in PG cells causes larval developmental arrest due to reduction in biosynthesis of the steroid hormone ecdysone. Moreover, inhibition of the nutrient sensor target of rapamycin (TOR) in the PG during the checkpoint period causes endocycle inhibition and developmental arrest, which can be rescued by inducing additional rounds of endocycles by Cyclin E. We propose that a TOR-mediated cell cycle checkpoint in steroidogenic tissue provides a systemic growth checkpoint for reproductive maturation. Onset of sexual maturation constitutes a point of no return in animals; once this life-changing decision is made, upregulation of steroidogenesis leads to irreversible juvenile-to-adult transition in humans and insects alike. While nutrient signals contributing to this decision-making process have been well studied, molecular events that ultimately determine its precise timing remain a mystery. We report here that nutrient-dependent endoreplication, the replication of genomic DNA without cell division, in steroidogenic cells functions as an intrinsic timer, whereby degree of polyploidy sets the timing of reproductive maturation (i.e. metamorphosis) in fruit flies. The cumulative and irreversible nature of endoreplication thus provides an intrinsic molecular machinery underlying the irreversible decision-making process, which may be widely leveraged as a fundamental developmental timing mechanism.