title: WIDE AWAKE mediates the circadian timing of sleep onset.
abstract: How the circadian clock regulates the timing of sleep is poorly understood. Here, we identify a Drosophila mutant, wide awake (wake), that exhibits a marked delay in sleep onset at dusk. Loss of WAKE in a set of arousal-promoting clock neurons, the large ventrolateral neurons (l-LNvs), impairs sleep onset. WAKE levels cycle, peaking near dusk, and the expression of WAKE in l-LNvs is Clock dependent. Strikingly, Clock and cycle mutants also exhibit a profound delay in sleep onset, which can be rescued by restoring WAKE expression in LNvs. WAKE interacts with the GABAA receptor Resistant to Dieldrin (RDL), upregulating its levels and promoting its localization to the plasma membrane. In wake mutant l-LNvs, GABA sensitivity is decreased and excitability is increased at dusk. We propose that WAKE acts as a clock output molecule specifically for sleep, inhibiting LNvs at dusk to promote the transition from wake to sleep.
authors.affiliation: Department of Neurology, Johns Hopkins University, Baltimore, MD 21287, USA.
authors.forename: Sha
authors.initials: S
authors.lastname: Liu
authors.affiliation: Department of Neuroscience and the Farber Institute for Neurosciences, Thomas Jefferson University, Philadelphia, PA 19107, USA.
authors.forename: Angelique
authors.initials: A
authors.lastname: Lamaze
authors.affiliation: Department of Neurology, Johns Hopkins University, Baltimore, MD 21287, USA.
authors.forename: Qili
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Department of Neurology, Johns Hopkins University, Baltimore, MD 21287, USA.
authors.forename: Masashi
authors.initials: M
authors.lastname: Tabuchi
authors.affiliation: Department of Neuroscience and the Farber Institute for Neurosciences, Thomas Jefferson University, Philadelphia, PA 19107, USA.
authors.forename: Yong
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Biological Chemistry, Johns Hopkins University, Baltimore, MD 21287, USA.
authors.forename: Melissa
authors.initials: M
authors.lastname: Fowler
authors.affiliation: Department of Neurology, Johns Hopkins University, Baltimore, MD 21287, USA.
authors.forename: Rajnish
authors.initials: R
authors.lastname: Bharadwaj
authors.affiliation: Department of Neurology, Johns Hopkins University, Baltimore, MD 21287, USA.
authors.forename: Julia
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Neuroscience, Johns Hopkins University, Baltimore, MD 21287, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Bedont
authors.affiliation: Department of Neuroscience, Johns Hopkins University, Baltimore, MD 21287, USA.
authors.forename: Seth
authors.initials: S
authors.lastname: Blackshaw
authors.affiliation: Department of Neurology, Johns Hopkins University, Baltimore, MD 21287, USA; Department of Neuroscience, Johns Hopkins University, Baltimore, MD 21287, USA.
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Lloyd
authors.affiliation: Neuroscience Research Institute and Department of Molecular, Cellular, & Developmental Biology, University of California, Santa Barbara, Santa Barbara, CA 93106, USA.
authors.forename: Craig
authors.initials: C
authors.lastname: Montell
authors.affiliation: Howard Hughes Medical Institute, Department of Neuroscience, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Amita
authors.initials: A
authors.lastname: Sehgal
authors.affiliation: Department of Neuroscience and the Farber Institute for Neurosciences, Thomas Jefferson University, Philadelphia, PA 19107, USA. Electronic address: kyunghee.koh@jefferson.edu.
authors.forename: Kyunghee
authors.initials: K
authors.lastname: Koh
authors.affiliation: Department of Neurology, Johns Hopkins University, Baltimore, MD 21287, USA; Department of Neuroscience, Johns Hopkins University, Baltimore, MD 21287, USA. Electronic address: marknwu@jhmi.edu.
authors.forename: Mark N
authors.initials: MN
authors.lastname: Wu
mesh_terms: D056930:ARNTL Transcription Factors / Q000235:genetics; D000818:Animals; D030801:Animals, Genetically Modified; D001921:Brain / Q000166:cytology; D056926:CLOCK Proteins / Q000235:genetics; D002940:Circadian Rhythm / Q000187:drug effects / Q000502:physiology*; D056925:Circadian Rhythm Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D004330:Drosophila; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics; D006727:Hormone Antagonists / Q000494:pharmacology; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D015735:Mifepristone / Q000494:pharmacology; D009154:Mutation / Q000235:genetics; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D011930:Reaction Time / Q000235:genetics; D012890:Sleep / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D013997:Time Factors
chemical_list: D056930:ARNTL Transcription Factors; D056925:Circadian Rhythm Signaling Peptides and Proteins; C120526:Clk protein, Drosophila; D029721:Drosophila Proteins; D006727:Hormone Antagonists; D008164:Luminescent Proteins; C000588663:Wake protein, Drosophila; C112805:cyc protein, Drosophila; D049452:Green Fluorescent Proteins; D015735:Mifepristone; D056926:CLOCK Proteins