Journal article
Conserved properties of Drosophila Insomniac link sleep regulation and synaptic function
PLoS genetics, Vol.13(5), pp.e1006815-e1006815
05/2017
DOI: 10.1371/journal.pgen.1006815
PMCID: PMC5469494
PMID: 28558011
Abstract
Sleep is an ancient animal behavior that is regulated similarly in species ranging from flies to humans. Various genes that regulate sleep have been identified in invertebrates, but whether the functions of these genes are conserved in mammals remains poorly explored. Drosophila insomniac (inc) mutants exhibit severely shortened and fragmented sleep. Inc protein physically associates with the Cullin-3 (Cul3) ubiquitin ligase, and neuronal depletion of Inc or Cul3 strongly curtails sleep, suggesting that Inc is a Cul3 adaptor that directs the ubiquitination of neuronal substrates that impact sleep. Three proteins similar to Inc exist in vertebrates-KCTD2, KCTD5, and KCTD17-but are uncharacterized within the nervous system and their functional conservation with Inc has not been addressed. Here we show that Inc and its mouse orthologs exhibit striking biochemical and functional interchangeability within Cul3 complexes. Remarkably, KCTD2 and KCTD5 restore sleep to inc mutants, indicating that they can substitute for Inc in vivo and engage its neuronal targets relevant to sleep. Inc and its orthologs localize similarly within fly and mammalian neurons and can traffic to synapses, suggesting that their substrates may include synaptic proteins. Consistent with such a mechanism, inc mutants exhibit defects in synaptic structure and physiology, indicating that Inc is essential for both sleep and synaptic function. Our findings reveal that molecular functions of Inc are conserved through ~600 million years of evolution and support the hypothesis that Inc and its orthologs participate in an evolutionarily conserved ubiquitination pathway that links synaptic function and sleep regulation.
Details
- Title: Subtitle
- Conserved properties of Drosophila Insomniac link sleep regulation and synaptic function
- Creators
- Qiuling Li - Neuroscience Institute, Department of Neuroscience and Physiology, New York University School of Medicine, New York, NY, United States of AmericaDavid A Kellner - Neuroscience Institute, Department of Neuroscience and Physiology, New York University School of Medicine, New York, NY, United States of AmericaHayden A M Hatch - Neuroscience Institute, Department of Neuroscience and Physiology, New York University School of Medicine, New York, NY, United States of AmericaTomohiro Yumita - Neuroscience Institute, Department of Neuroscience and Physiology, New York University School of Medicine, New York, NY, United States of AmericaSandrine Sanchez - Neuroscience Institute, Department of Neuroscience and Physiology, New York University School of Medicine, New York, NY, United States of AmericaRobert P Machold - Neuroscience Institute, Department of Neuroscience and Physiology, New York University School of Medicine, New York, NY, United States of AmericaC Andrew Frank - Interdisciplinary Programs in Genetics, Neuroscience, and MCB, University of Iowa, Iowa City, IA, United States of AmericaNicholas Stavropoulos - Neuroscience Institute, Department of Neuroscience and Physiology, New York University School of Medicine, New York, NY, United States of America
- Resource Type
- Journal article
- Publication Details
- PLoS genetics, Vol.13(5), pp.e1006815-e1006815
- DOI
- 10.1371/journal.pgen.1006815
- PMID
- 28558011
- PMCID
- PMC5469494
- NLM abbreviation
- PLoS Genet
- ISSN
- 1553-7390
- eISSN
- 1553-7404
- Publisher
- Public Library Science; United States
- Grant note
- DOI: 10.13039/100000011, name: Howard Hughes Medical Institute, award: International Student Research Fellowship; DOI: 10.13039/100000002, name: National Institutes of Health, award: NS062738; DOI: 10.13039/100001391, name: Whitehall Foundation, award: 2014-08-03; DOI: 10.13039/100001391, name: Whitehall Foundation, award: 2013-05-78; DOI: 10.13039/100000879, name: Alfred P. Sloan Foundation; DOI: 10.13039/100007027, name: Leon Levy Foundation; DOI: 10.13039/100001229, name: G. Harold and Leila Y. Mathers Charitable Foundation; DOI: 10.13039/100000874, name: Brain and Behavior Research Foundation, award: NARSAD Young Investigator; DOI: 10.13039/100006732, name: New York University, award: Whitehead Fellowship; DOI: 10.13039/100009365, name: Sleep Research Society, award: J. Christian Gillin, M.D. Research Award
- Language
- English
- Date published
- 05/2017
- Academic Unit
- Anatomy and Cell Biology; Iowa Neuroscience Institute; Biology
- Record Identifier
- 9984070522202771
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