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About the Authors:
Bridget C. Lear
* E-mail: [email protected]
Affiliation: Department of Biology, University of Iowa, Iowa City, Iowa, United States of America
Eric J. Darrah
Affiliation: Department of Biology, University of Iowa, Iowa City, Iowa, United States of America
Benjamin T. Aldrich
Affiliation: Department of Biology, University of Iowa, Iowa City, Iowa, United States of America
Senetibeb Gebre
Affiliation: Department of Biology, University of Iowa, Iowa City, Iowa, United States of America
Robert L. Scott
Affiliation: Laboratory of Molecular Biology, National Institute of Mental Health, Bethesda, Maryland, United States of America
Howard A. Nash
† Deceased.
Affiliation: Laboratory of Molecular Biology, National Institute of Mental Health, Bethesda, Maryland, United States of America
Ravi Allada
Affiliation: Department of Neurobiology, Northwestern University, Evanston, Illinois, United States of America
Introduction
Circadian rhythms are daily patterns of behavior and physiology driven by cellular clocks. Circadian clocks in metazoans consist of interdependent transcriptional feedback loops and post-translational modifications that produce ∼24 hour molecular oscillations. At the core of the Drosophila circadian clock, the transcription factor partners CLOCK (CLK) and CYCLE (CYC) upregulate the expression of period (per) and timeless (tim). PER and TIM proteins accumulate in the cytoplasm and later translocate to the nucleus, where they inhibit CLK-CYC activity and their own expression. This mechanism and others result in ∼24 hour rhythms in CLK-CYC transcription factor activity and in PER/TIM expression. This molecular clock is highly conserved in animals, and homologs of several Drosophila clock genes exhibit similar functions in mammals [1]. In Drosophila, the molecular clocks essential for daily activity rhythms are found in roughly 150 pacemaker neurons in the adult brain, and specific groups of these neurons have been shown to be important for different aspects of behavioral rhythmicity. A subset of pacemaker neurons express the neuropeptide Pigment-Dispersing Factor (PDF), and the PDF+ cells communicate to a broader group of pacemaker neurons to synchronize and enhance molecular clock oscillations [2].
An important component of circadian pacemaker neuronal output in Drosophila is NARROW ABDOMEN (NA), a putative sodium leak channel orthologous to mammalian NALCN. Drosophila na mutants exhibit strong defects in circadian locomotor behavior, as well as increased anesthetic sensitivity and “hesitant” walking [3]. Despite disruptions in circadian behavior, oscillations of the clock protein PER remain essentially...