The role of RNA binding proteins in the control of Drosophila circadian rhythms

描述（由申请人提供）：昼夜节律对大多数动物至关重要，因为它们确保其生理、代谢和行为适当适应并与昼夜周期同步。昼夜节律在动物中通过充分表征的转录反馈环产生。一组激酶和磷酸酶负责参与该环的转录因子的翻译后控制。中间水平的调节，如mRNA的稳定性和翻译控制的作用迄今为止很少受到关注，虽然有越来越多的证据表明，这样的调节机制确实影响昼夜节律。我们的目标是了解RNA结合蛋白在果蝇昼夜节律行为控制中所起的作用。我们将重点关注GW 182和ATX 2。事实上，我们的初步数据表明，这两个RNA结合蛋白发挥关键的昼夜节律功能。ATX 2调节昼夜节律起搏器的节奏，而GW 182是调节大脑昼夜节律神经元的PDF/PDFR信号通路的一部分。我们的第一个目标是精确定义GW 182的昼夜节律功能，并确定它如何与PDFR通路相互作用。我们的第二个目标是确定GW 182影响昼夜节律行为的分子机制。最后，我们的第三个目标是确定ATX 2在昼夜节律起搏器中的确切作用，以及其昼夜节律功能的机制。总之，这三个目标将揭示控制昼夜节律的全新机制。我们的工作很可能对我们理解哺乳动物和人类的昼夜节律有重要意义。事实上，ATX 2和GW 182都是参与保守昼夜节律途径的进化保守分子：昼夜节律分子起搏器在哺乳动物和果蝇中非常相似，而PDF/PDFR信号传导途径是哺乳动物VIP/VIPR途径的功能和分子同源物，该途径使昼夜节律同步视交叉上核中的神经元。昼夜节律紊乱是人类重要的心理和躯体疾病的原因，特别是在轮班工人和患有特定情绪和睡眠障碍的患者中。因此，我们的工作最终应该有助于了解这些疾病的生物学基础。通过了解ATX 2在昼夜节律背景下的细胞功能，我们的工作还应该揭示ATX 2控制基因表达的新机制。因此，我们的工作可能会影响我们对神经退行性疾病机制的理解，因为ATX 2与脊髓小脑共济失调有关。

DESCRIPTION (provided by applicant): Circadian rhythms are critically important for most animals, because they ensure that their physiology, metabolism and behavior is properly adapted to and synchronized with the day/night cycle. Circadian rhythms are generated in animals by a well-characterized transcriptional feedback loop. A set of kinases and phosphatases is responsible for the post-translational control of the transcription factors engaged in this loop. The role of intermediate levels of regulation such as mRNA stability and translational control have so far received little attention, although there is increasing evidence that such regulatory mechanisms do affect circadian rhythms. Our goal is to understand the role played by RNA binding proteins in the control of Drosophila circadian behavior. We will focus on GW182 and ATX2. Indeed, our preliminary data show that these two RNA binding proteins play crucial circadian functions. ATX2 regulates the pace of the circadian pacemaker, while GW182 is part of the PDF/PDFR signaling pathway that synchronizes brain circadian neurons. With our first aim, we will precisely define the circadian function of GW182 and determine how it interacts with the PDFR pathway. With our second aim, we will determine by which molecular mechanisms GW182 affects circadian behavior. Finally, with our third aim, we will determine the exact role of ATX2 in the circadian pacemaker, and the mechanisms underlying its circadian function. Together, these three aims will reveal completely novel mechanisms controlling circadian rhythms. Our work will most likely have important implications for our understanding of mammalian and human circadian rhythms. Indeed, both ATX2 and GW182 are evolutionary conserved molecules involved in conserved circadian pathways: the circadian molecular pacemaker is remarkably similar in mammals and Drosophila, while the PDF/PDFR signaling pathway is the functional and molecular homolog of the mammalian VIP/VIPR pathway, which synchronizes circadian neurons in the suprachiasmatic nucleus. Disrupted circadian rhythms are responsible for important psychological and somatic ailments in humans, particularly in shift worker and in patients with specific mood and sleep disorders. Our work should thus ultimately help understanding of the biological bases of these diseases. By understanding the cellular function of ATX2 in the context of circadian rhythms, our work should also reveal novel mechanisms by which ATX2 controls gene expression. Our work might thus impact our understanding of the mechanisms underlying neurodegenerative diseases, since ATX2 is implicated in spinocerebellar ataxia.