Scaling the Drosophila Wing: TOR-Dependent Target Gene Access by the Hippo Pathway Transducer Yorkie.
Scaling the Drosophila Wing: TOR-Dependent Target Gene Access by the Hippo Pathway Transducer Yorkie.
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DOI：
10.1371/journal.pbio.1002274
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发表时间：
2015-10
期刊：
影响因子：
9.8
通讯作者：
Struhl G
中科院分区：
文献类型：
--
作者：
Parker J;Struhl G
器官的生长由局部运作的模式信号(例如，Wingless/Ints[WNTS]、BMPs[BMPs]和Hedgehars[HHS])控制，并由系统作用的营养相关信号(例如，雷帕霉素[TOR]途径转导的胰岛素样肽[ILPS])调节。细胞如何整合这些不同的输入，以产生合适大小和形状的器官，在很大程度上是未知的。转录共激活因子yorkie(yki，一种YES相关蛋白，或YAP)作用于构图形态原和其他组织固有信号的下游，促进器官生长。YKI的活性主要受WATS/HPO(WATS/HPO)肿瘤抑制通路的调节，该通路通过细胞质的拴系机制阻碍YKI的核通路。在这里，我们展示了在果蝇的翅膀中，TOR通路通过一种独立的和新的机制来调节yki。TOR信号不是控制yki核的访问，而是在yki到达细胞核后通过允许其访问其目标基因来管理yki的活动。当TOR活性被抑制时，yki在细胞核内积累，但与其正常的促进生长的目标基因隔离--我们将这种现象称为“核隔离”。因此，我们假设TOR除了在刺激细胞新陈代谢对营养物质的反应方面具有众所周知的作用外，还通过将yki从核隔离中解放出来促进翅膀生长，我们提出的这一平行途径有助于随着营养物质的可获得性而扩大翅膀尺寸。从侏儒到巨人，鳞片是动物器官的普遍属性，但其机制基础却鲜为人知。在这里，作者发现了果蝇翅膀伸缩的分子回路。是什么机制控制着动物器官的大小？众所周知，器官生长是两个系统的产物：一个内在系统协调细胞增殖与指定细胞命运(图案化)，另一个外在系统使生长与营养水平同步。发育中的器官将这两个输入整合在一起，以确保发育出适当比例的结构，这些结构具有与整体身体尺寸相匹配的适当规模。然而，用于整合这些不同的生长控制系统的机制在很大程度上仍然是个谜。在这项研究中，我们讨论了内部和外部系统如何结合在一起来驱动果蝇翅膀的生长。聚焦于雷帕霉素(TOR)途径的靶标(TOR)途径--一个主要的、依赖于营养的器官生长调节因子--和约克--河马途径下游的转录激活因子和一个关键的器官内在生长调节因子--我们已经确定了一个回路，在这个回路中，TOR活性限制了约克促进翅膀生长的能力，部分是通过一种新的转录因子调节模式，我们称之为“核隔离”。我们发现，抑制TOR导致约克病毒保留在细胞核中，但通过转移它的靶基因而降低了它的转录活性。我们假设，以这种方式征服约克有助于TOR活动的波动，根据营养水平来衡量翅膀的大小。
Organ growth is controlled by patterning signals that operate locally (e.g., Wingless/Ints [Wnts], Bone Morphogenetic Proteins [BMPs], and Hedgehogs [Hhs]) and scaled by nutrient-dependent signals that act systemically (e.g., Insulin-like peptides [ILPs] transduced by the Target of Rapamycin [TOR] pathway). How cells integrate these distinct inputs to generate organs of the appropriate size and shape is largely unknown. The transcriptional coactivator Yorkie (Yki, a YES-Associated Protein, or YAP) acts downstream of patterning morphogens and other tissue-intrinsic signals to promote organ growth. Yki activity is regulated primarily by the Warts/Hippo (Wts/Hpo) tumour suppressor pathway, which impedes nuclear access of Yki by a cytoplasmic tethering mechanism. Here, we show that the TOR pathway regulates Yki by a separate and novel mechanism in the Drosophila wing. Instead of controlling Yki nuclear access, TOR signaling governs Yki action after it reaches the nucleus by allowing it to gain access to its target genes. When TOR activity is inhibited, Yki accumulates in the nucleus but is sequestered from its normal growth-promoting target genes—a phenomenon we term “nuclear seclusion.” Hence, we posit that in addition to its well-known role in stimulating cellular metabolism in response to nutrients, TOR also promotes wing growth by liberating Yki from nuclear seclusion, a parallel pathway that we propose contributes to the scaling of wing size with nutrient availability. From dwarves to giants, scaling is a universal property of animal organs, but its mechanistic basis is poorly understood. Here, the authors identify a molecular circuit underlying scaling of the Drosophila wing. What mechanisms control the sizes of animal organs? It is known that organ growth is the product of two systems: an intrinsic system that coordinates cell proliferation with the specification of cell fate (patterning), and an extrinsic system that synchronizes growth with nutrient levels. Developing organs integrate these two inputs to ensure that properly proportioned structures develop which are of the right scale to match overall body size. However, the mechanisms used to integrate these distinct growth control systems have remained largely mysterious. In this study, we have addressed how intrinsic and extrinsic systems combine to drive growth of the Drosophila wing. Focusing on the Target of Rapamycin (TOR) pathway—a major, nutrient-dependent regulator of organ growth—and Yorkie—the transcriptional activator downstream of the Hippo pathway and a key, organ-intrinsic growth regulator—we have identified a circuit in which TOR activity limits Yorkie’s capacity to promote wing growth, in part through a novel mode of transcription factor regulation that we term “nuclear seclusion.” We find that inhibiting TOR leads to the retention of Yorkie in the nucleus but diminishes its transcriptional activity by diverting it away from target genes. We posit that subjugating Yorkie in this way contributes to how fluctuations in TOR activity scale wing size according to nutrient levels.