dDOR Is an EcR Coactivator that Forms a Feed-Forward Loop Connecting Insulin and Ecdysone Signaling
dDOR Is an EcR Coactivator that Forms a Feed-Forward Loop Connecting Insulin and Ecdysone Signaling
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DOI：
10.1016/j.cub.2010.08.055
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发表时间：
2010-10-26
期刊：
影响因子：
9.2
通讯作者：
Teleman, Aurelio A.
中科院分区：
文献类型：
--
作者：
Francis, Victor A.;Zorzano, Antonio;Teleman, Aurelio A.
背景：哺乳动物DOR基因是在Zucker糖尿病大鼠肌肉中发现的一个表达失调的基因。由于没有DOR功能丧失的哺乳动物模型，我们在这里分析的DOR在体内功能的果蝇DOR突变体（dDOR）的研究结果：我们表明，dDOR是一种新的辅激活剂蜕皮激素受体（EcR），需要在变态。dDOR与EcR结合，是最大EcR转录活性所需的。在缺乏dDOR的情况下，果蝇表现出许多蜕皮激素功能丧失的表型，如气门外翻受损、唾液腺降解受损和蛹致死。此外，dDOR敲除果蝇是精瘦的。我们发现dDOR的表达受到胰岛素信号通过FOXO的抑制。结论：这项工作揭示了dDOR作为一种新的EcR共激活剂。它还建立了蜕皮激素和胰岛素信号之间的相互拮抗关系，在苍蝇脂肪体。此外，由于蜕皮激素信号传导抑制脂肪体中的胰岛素信号传导，这也揭示了蜕皮激素通过dDOR增强其自身信号传导的前馈机制。
Background: Mammalian DOR was discovered as a gene whose expression is misregulated in muscle of Zucker diabetic rats. Because no DOR loss-of-function mammalian models are available, we analyze here the in vivo function of DOR by studying flies mutant for Drosophila DOR (dDOR).Results: We show that dDOR is a novel coactivator of ecdysone receptor (EcR) that is needed during metamorphosis. dDOR binds EcR and is required for maximal EcR transcriptional activity. In the absence of dDOR, flies display a number of ecdysone loss-of-function phenotypes such as impaired spiracle eversion, impaired salivary gland degradation, and pupal lethality. Furthermore, dDOR knockout flies are lean. We find that dDOR expression is inhibited by insulin signaling via FOXO.Conclusion: This work uncovers dDOR as a novel EcR coactivator. It also establishes a mutual antagonistic relationship between ecdysone and insulin signaling in the fly fat body. Furthermore, because ecdysone signaling inhibits insulin signaling in the fat body, this also uncovers a feed-forward mechanism whereby ecdysone potentiates its own signaling via dDOR.