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.

Public Health Relevance

Disruptions of circadian rhythms - which control our daily behavior and physiology - are responsible for various somatic and psychological diseases, for example in shift workers and in patients affected with specific sleep and mood disorders. Our work, focused on the role of RNA binding proteins in the control of Drosophila circadian rhythms, will reveal novel regulatory mechanisms controlling circadian clocks. Since the mechanisms underlying circadian rhythms are remarkably similar in Drosophila and mammals, our work should help understanding the biological bases of circadian rhythm-related diseases.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Neurodifferentiation, Plasticity, and Regeneration Study Section (NDPR)
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Sesma, Michael A
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University of Massachusetts Medical School Worcester
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Zhang, Yong; Lamba, Pallavi; Guo, Peiyi et al. (2016) miR-124 Regulates the Phase of Drosophila Circadian Locomotor Behavior. J Neurosci 36:2007-13
Tataroglu, Ozgur; Emery, Patrick (2015) The molecular ticks of the Drosophila circadian clock. Curr Opin Insect Sci 7:51-57
Tataroglu, Ozgur; Emery, Patrick (2014) Studying circadian rhythms in Drosophila melanogaster. Methods 68:140-50
Zhang, Yong; Emery, Patrick (2013) GW182 controls Drosophila circadian behavior and PDF-receptor signaling. Neuron 78:152-65
Zhang, Yong; Ling, Jinli; Yuan, Chunyan et al. (2013) A role for Drosophila ATX2 in activation of PER translation and circadian behavior. Science 340:879-82