Our prior work has focused on the molecular mechanisms underlying Drosophila?s circadian rhythms. Orthologs of genes initially characterized in Drosophila have now been linked to the control of rhythmic behavior and physiology in vertebrates, including fish, frogs, mice and humans. Here we prose four classes of interdisciplinary investigations of the fly?s rhythmic behavior. (1) We will extend a classical genetic screen (chemical mutagenesis) for mutations conferring aberrant activity/rest patterns. An X-chromosomal screen produced several mutant lines with effects on either sleep duration or phase. In future work, we will determine the identity of the affected genes, the cellular and molecular patterns of their expression, and will start a comparable screen on chromosomes 2 and 3. (2) We will characterize a novel, reduced- sleep mutant insomniac. These consistently rest for ~400 min/day, nearly 9 hours less than wild type. We will determine where insomniac is expressed within the brain, wheterh cells expressing insomniac have other roles in organizing sleep, and when insomniac function is required to determine sleep duration. (3) We have discovered that when Drosophila are maintained in a photocycle, period mRNA undergoes daily cycles of polyadenylation. The time of polyadenylation can be delayed by prolonged exposure to light. We will determine whether these responses provide a novel mechanism for day- length (seasonal) measurement.

Public Health Relevance

The pressing need to understand sleep is underscored by the major clinical and economic impact of sleep disorders;10-15% of the U.S. population suffers from chronic insomnia, and nearly one hundred disorders have been described, including narcolepsy, sleep apnea, and delayed and advanced sleep phase syndromes. Molecular genetic studies that began in Drosophila have already allowed mutant orthologs of Period protein and casein kinase 1 to be connected to inborn errors of human sleep. We believe our proposed genetic, cellular, and biochemical studies of Drosophila?s activity/rest behavior will continue to provide insights and tools relevant to the understanding of human sleep.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS053087-05
Application #
7780899
Study Section
Biological Rhythms and Sleep Study Section (BRS)
Program Officer
Mitler, Merrill
Project Start
2005-07-01
Project End
2012-02-28
Budget Start
2010-03-01
Budget End
2012-02-28
Support Year
5
Fiscal Year
2010
Total Cost
$825,073
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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