We have been studying the molecular control of circadian behavioral rhythms using Drosophila as a model system. Orthologs of genes initially characterized in the fly,have now been linked to the control of rhythmic behavior and physiology in vertebrates, including fish, frogs, mice and humans. Here we propose three classes of interdisciplinary investigations of the Drosophila clock. (1) We will conduct collaborative structural studies that can help us determine how specific regulatory actions, previously recognized genetically and biochemically, are performed by certain domains of the PER protein. Does the structure of PER indicate how it interacts with TIM and DBT? Do such data suggest how TIM suppresses PER's phosphorylation by DBT? Does a putative LOV domain near the N-terminus of PER possess a flavin binding domain? (2) We will generate new mutations for the analysis of vital clock genes by Conditional Protein Splicing. Our studies of hyper- and hypo-morphic mutations of GSK-3, dbt, vri, and Pdp-1 indicate that each is a key component of the Drosophila clock. However, because null mutations of these genes are lethal, it has been difficult to determine their full effects on the clock. We are developing a form of chemical genetics in which small diffusible molecules will reversibly control the presence of each vital protein in living flies. (3) We will produce new microarray and statistical approaches to clarify features of rhythmic genome activity and to determine if flies use a single molecular mechanism to generate all circadian rhythms. To begin to link the clock to specific behavioral and physiological outputs, we will investigate a novel set of genes that are regulated by a paired action of light and the circadian clock.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS053087-03
Application #
7354090
Study Section
Special Emphasis Panel (ZRG1-NCF (09))
Program Officer
Mitler, Merrill
Project Start
2006-02-03
Project End
2010-01-31
Budget Start
2008-02-01
Budget End
2009-01-31
Support Year
3
Fiscal Year
2008
Total Cost
$369,223
Indirect Cost
Name
Rockefeller University
Department
Genetics
Type
Other Domestic Higher Education
DUNS #
071037113
City
New York
State
NY
Country
United States
Zip Code
10065
Garaulet, Daniel L; Sun, Kailiang; Li, Wanhe et al. (2016) miR-124 Regulates Diverse Aspects of Rhythmic Behavior in Drosophila. J Neurosci 36:3414-21
Axelrod, Sofia; Saez, Lino; Young, Michael W (2015) Studying circadian rhythm and sleep using genetic screens in Drosophila. Methods Enzymol 551:3-27
Crane, Brian R; Young, Michael W (2014) Interactive features of proteins composing eukaryotic circadian clocks. Annu Rev Biochem 83:191-219
Rogulja, Dragana; Young, Michael W (2012) Control of sleep by cyclin A and its regulator. Science 335:1617-21
Saez, Lino; Derasmo, Mary; Meyer, Pablo et al. (2011) A key temporal delay in the circadian cycle of Drosophila is mediated by a nuclear localization signal in the timeless protein. Genetics 188:591-600
Stavropoulos, Nicholas; Young, Michael W (2011) insomniac and Cullin-3 regulate sleep and wakefulness in Drosophila. Neuron 72:964-76
Syed, Sheyum; Saez, Lino; Young, Michael W (2011) Kinetics of doubletime kinase-dependent degradation of the Drosophila period protein. J Biol Chem 286:27654-62
King, Heather A; Hoelz, André; Crane, Brian R et al. (2011) Structure of an enclosed dimer formed by the Drosophila period protein. J Mol Biol 413:561-72
Kivimae, Saul; Saez, Lino; Young, Michael W (2008) Activating PER repressor through a DBT-directed phosphorylation switch. PLoS Biol 6:e183
Boothroyd, Catharine E; Wijnen, Herman; Naef, Felix et al. (2007) Integration of light and temperature in the regulation of circadian gene expression in Drosophila. PLoS Genet 3:e54

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