Molecular and Neural Mechanisms of Sleep Regulation by TARANIS

Thomas Jefferson University, Philadelphia PA

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Abstract

? DESCRIPTION (provided by applicant): Sleep serves essential biological functions, and is conserved from flies to humans. Sleep disturbance is a common health problem that impinges on quality of life, workplace productivity, and public safety. Sleep usually occurs at specific tims of day and lasts for certain amounts of time. These two features of sleep are controlled by distinct molecular mechanisms. Whereas the molecular and anatomical basis of the circadian clock, which controls when we sleep, has been investigated extensively, the molecules and neural circuits underlying sleep homeostasis that regulates sleep duration are not well understood. Identification of novel genes and circuits that control sleep duration would facilitate elucidation of this mysterious biological process. The Drosophila model for sleep is well suited for discovery of new sleep-modulating genes through unbiased genetic screens. Using a forward-genetic screen for short-sleeping mutants, we isolated a novel sleep gene, taranis (tara). Mutations in tara result in a marked (up to 80%) reduction of sleep duration. [[Importantly tara mutants exhibit decreased levels of REDEYE (RYE), whose expression is regulated by homeostatic sleep drive. Thus isolation of TARA provides an exciting opportunity to investigate the molecular mechanisms underlying sleep homeostasis, a critical process that is poorly understood. Previous findings suggest that TARA and its mammalian homologs are involved in transcriptional regulation and cell cycle progression, and contain a Cyclin A (CycA)-binding homology domain. Notably, CycA, another cell cycle protein, was recently shown to be a sleep-promoting factor, but the molecular function of CycA in sleep is not well understood. Our preliminary studies suggest that TARA promotes sleep by two complementary pathways: 1) by upregulating protein expression of CycA and inhibiting Cdk1 (a Cyclin-dependent kinase that binds CycA and negative regulator of sleep), and 2) by upregulating transcription of dawdle (daw), an Activin-like signaling molecule and positive regulator of sleep. Further, our data identify ~14 CycA expressing cells in the pars lateralis (PL), which is analogous to the mammalian hypothalamus, as a novel sleep center. Building on these preliminary data, we propose to (Aim 1) determine how TARA interacts with other cell cycle proteins to regulate sleep, (Aim 2) how TARA interacts with daw to regulate sleep, and whether DAW acts as a sleep-inducing homeostatic signal, and (Aim 3) determine where and when TARA is required for sleep, and how the PL neurons connect to other sleep centers. The proposed experiments will yield significant mechanistic insights into sleep homeostasis.]]