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      A Homeostatic Sleep-Stabilizing Pathway in Drosophila Composed of the Sex Peptide Receptor and Its Ligand, the Myoinhibitory Peptide

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          A ligand of the sex peptide receptor maintains sleep stability and homeostasis by inhibiting wakefulness-promoting neurons in Drosophila.


          Sleep, a reversible quiescent state found in both invertebrate and vertebrate animals, disconnects animals from their environment and is highly regulated for coordination with wakeful activities, such as reproduction. The fruit fly, Drosophila melanogaster, has proven to be a valuable model for studying the regulation of sleep by circadian clock and homeostatic mechanisms. Here, we demonstrate that the sex peptide receptor (SPR) of Drosophila, known for its role in female reproduction, is also important in stabilizing sleep in both males and females. Mutants lacking either the SPR or its central ligand, myoinhibitory peptide (MIP), fall asleep normally, but have difficulty in maintaining a sleep-like state. Our analyses have mapped the SPR sleep function to pigment dispersing factor ( pdf) neurons, an arousal center in the insect brain. MIP downregulates intracellular cAMP levels in pdf neurons through the SPR. MIP is released centrally before and during night-time sleep, when the sleep drive is elevated. Sleep deprivation during the night facilitates MIP secretion from specific brain neurons innervating pdf neurons. Moreover, flies lacking either SPR or MIP cannot recover sleep after the night-time sleep deprivation. These results delineate a central neuropeptide circuit that stabilizes the sleep state by feeding a slow-acting inhibitory input into the arousal system and plays an important role in sleep homeostasis.

          Author Summary

          Sleep is a common trait in animals, from insects to mammals, and it needs to be coordinated with other critical activities such as feeding and reproduction. However, the mechanisms by which this is achieved are not fully understood. The fruit fly Drosophila melanogaster has become a key model organism for sleep research and it has been shown that reproduction is one of the factors that can modulate sleep in these animals. Researchers have observed that mating reduces the daytime sleep of female flies and shown that the seminal fluid protein Sex Peptide (SP), a ligand of the Sex Peptide Receptor (SPR) that is transferred to females during copulation, is responsible for this reduction of siesta sleep. Here, we investigated further the role of SPR in sleep regulation in Drosophila. We show that SPR is required for sleep stabilization in both sexes and that in mutant flies lacking SPR or its ligand myoinhibitory peptide (MIP) sleep is fragmented independently of reproduction. Unlike SP, MIP is expressed in the brain of both sexes and acts on SPR to silence specific neurons that keep flies awake, stabilizing sleep. Hence, our results reveal that SPR interacts with two distinct ligands to control different behaviors: SP for reproduction and MIP for sleep.

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          Most cited references 72

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          NIH Image to ImageJ: 25 years of image analysis.

          For the past 25 years NIH Image and ImageJ software have been pioneers as open tools for the analysis of scientific images. We discuss the origins, challenges and solutions of these two programs, and how their history can serve to advise and inform other software projects.
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            A genome-wide transgenic RNAi library for conditional gene inactivation in Drosophila.

            Forward genetic screens in model organisms have provided important insights into numerous aspects of development, physiology and pathology. With the availability of complete genome sequences and the introduction of RNA-mediated gene interference (RNAi), systematic reverse genetic screens are now also possible. Until now, such genome-wide RNAi screens have mostly been restricted to cultured cells and ubiquitous gene inactivation in Caenorhabditis elegans. This powerful approach has not yet been applied in a tissue-specific manner. Here we report the generation and validation of a genome-wide library of Drosophila melanogaster RNAi transgenes, enabling the conditional inactivation of gene function in specific tissues of the intact organism. Our RNAi transgenes consist of short gene fragments cloned as inverted repeats and expressed using the binary GAL4/UAS system. We generated 22,270 transgenic lines, covering 88% of the predicted protein-coding genes in the Drosophila genome. Molecular and phenotypic assays indicate that the majority of these transgenes are functional. Our transgenic RNAi library thus opens up the prospect of systematically analysing gene functions in any tissue and at any stage of the Drosophila lifespan.
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              Construction of transgenic Drosophila by using the site-specific integrase from phage phiC31.

              The phiC31 integrase functions efficiently in vitro and in Escherichia coli, yeast, and mammalian cells, mediating unidirectional site-specific recombination between its attB and attP recognition sites. Here we show that this site-specific integration system also functions efficiently in Drosophila melanogaster in cultured cells and in embryos. Intramolecular recombination in S2 cells on transfected plasmid DNA carrying the attB and attP recognition sites occurred at a frequency of 47%. In addition, several endogenous pseudo attP sites were identified in the fly genome that were recognized by the integrase and used as substrates for integration in S2 cells. Two lines of Drosophila were created by integrating an attP site into the genome with a P element. phiC31 integrase injected into embryos as mRNA functioned to promote integration of an attB-containing plasmid into the attP site, resulting in up to 55% of fertile adults producing transgenic offspring. A total of 100% of these progeny carried a precise integration event at the genomic attP site. These experiments demonstrate the potential for precise genetic engineering of the Drosophila genome with the phiC31 integrase system and will likely benefit research in Drosophila and other insects.

                Author and article information

                [1 ]Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, South Korea
                [2 ]School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, South Korea
                [3 ]Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, Michigan, United States of America
                Washington University, United States of America
                Author notes

                The authors have declared that no competing interests exist.

                The author(s) have made the following declarations about their contributions: Conceived and designed the experiments: Y-JK JC YO. Performed the experiments: YO S-EY QZ H-SC ID. Analyzed the data: Y-JK JC YO S-EY OTS. Wrote the paper: Y-JK JC YO.

                Role: Academic Editor
                PLoS Biol
                PLoS Biol
                PLoS Biology
                Public Library of Science (San Francisco, USA )
                October 2014
                21 October 2014
                : 12
                : 10
                25333796 4204809 PBIOLOGY-D-14-00444 10.1371/journal.pbio.1001974

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                Pages: 15
                Y-J.K. was supported by Basic Science Research Programs through the National Research Foundation of Korea (NRF) funded by Ministry of Science, ICT and Future Planning (MSIP), the Republic of Korea (NRF-2009-0089247, NRF-2011-0019291, NRF-2011-0018559). J.C. was supported by a NRF grant funded by MSIP (NRF-2011-0015442). O.T.S. was supported by NIH (NINDS) R01NS077933. 2012 GIST Systems Biology Infrastructure Establishment funded for the confocal imaging facility used in this study. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Research Article
                Biology and Life Sciences
                Peptide Hormones
                Evolutionary Biology
                Physiological Processes
                Behavioral Neuroscience
                Animal Behavior

                Life sciences


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