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

描述(申请人提供)：昼夜节律对大多数动物来说是至关重要的，因为它们确保它们的生理、新陈代谢和行为适当地适应并与昼夜周期同步。动物体内的昼夜节律是由一个特征明确的转录反馈环路产生的。一组激酶和磷酸酶负责参与这个环的转录因子的翻译后控制。尽管越来越多的证据表明，这种调节机制确实会影响昼夜节律，但到目前为止，中等水平的调控机制，如mRNA稳定性和翻译控制，所起的作用几乎没有受到关注。我们的目标是了解RNA结合蛋白在控制果蝇昼夜行为中所起的作用。我们将重点关注GW182和ATX2。事实上，我们的初步数据表明，这两个RNA结合蛋白发挥着至关重要的昼夜节律功能。ATX2调节昼夜节律起搏器的节奏，而GW182是PDF/PDFR信号通路的一部分，该信号通路同步大脑昼夜节律神经元。在我们的第一个目标中，我们将精确地定义GW182的昼夜节律功能，并确定它如何与PDFR途径相互作用。在我们的第二个目标中，我们将确定GW182通过哪些分子机制影响昼夜行为。最后，为了我们的第三个目标，我们将确定ATX2在昼夜节律起搏器中的确切作用，以及其昼夜节律功能的潜在机制。这三个目标加在一起，将揭示控制昼夜节律的全新机制。我们的工作很可能会对我们理解哺乳动物和人类的昼夜节律产生重要的影响。事实上，ATX2和GW182都是进化上保守的分子，参与保守的昼夜节律通路：哺乳动物和果蝇的昼夜节律分子起搏器非常相似，而PDF/PDFR信号通路是哺乳动物VIP/VIPR通路的功能和分子同源，后者使视交叉上核中的昼夜节律神经元同步。昼夜节律紊乱是人类重要的心理和躯体疾病的原因，特别是在倒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理解这些疾病的生物学基础。通过了解ATX2在昼夜节律背景下的细胞功能，我们的工作也应该揭示ATX2控制基因表达的新机制。我们的工作可能因此影响我们对神经退行性疾病潜在机制的理解，因为ATX2与脊髓-小脑性共济失调有关。

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.