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Nature. 2016 Nov 17;539(7629):378-383. doi: 10.1038/nature20142. Epub 2016 Nov 2.

Forward-genetics analysis of sleep in randomly mutagenized mice.

Author information

1
International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan.
2
Department of Anatomy, Faculty of Medicine, Toho University, Ota-ku, Tokyo 143-8540, Japan.
3
Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
4
Department of Neuropharmacology, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Aichi 467-8603, Japan.
5
Laboratory Animal Resource Center, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan.
6
Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
7
The Jackson Laboratory, Bar Harbor, Maine 04609, USA.
8
Technology and Development Team for Mouse Phenotype Analysis, RIKEN Bioresource Center, Tsukuba, Ibaraki 305-0074, Japan.
9
Laboratory of Research Advancement, National Center for Geriatrics and Gerontology, Obu, Aichi 474-8511, Japan.
10
Department of Cellular Neurobiology, Brain Research Institute, Niigata University, Niigata 951-8585, Japan.
11
PRESTO, Japan Science and Technology Agency, Kawaguchi, Saitama 332-0012, Japan.
12
Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
13
Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
14
Life Science Center, Tsukuba Advanced Research Alliance, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan.

Abstract

Sleep is conserved from invertebrates to vertebrates, and is tightly regulated in a homeostatic manner. The molecular and cellular mechanisms that determine the amount of rapid eye movement sleep (REMS) and non-REMS (NREMS) remain unknown. Here we identify two dominant mutations that affect sleep and wakefulness by using an electroencephalogram/electromyogram-based screen of randomly mutagenized mice. A splicing mutation in the Sik3 protein kinase gene causes a profound decrease in total wake time, owing to an increase in inherent sleep need. Sleep deprivation affects phosphorylation of regulatory sites on the kinase, suggesting a role for SIK3 in the homeostatic regulation of sleep amount. Sik3 orthologues also regulate sleep in fruitflies and roundworms. A missense, gain-of-function mutation in the sodium leak channel NALCN reduces the total amount and episode duration of REMS, apparently by increasing the excitability of REMS-inhibiting neurons. Our results substantiate the use of a forward-genetics approach for studying sleep behaviours in mice, and demonstrate the role of SIK3 and NALCN in regulating the amount of NREMS and REMS, respectively.

PMID:
27806374
PMCID:
PMC6076225
DOI:
10.1038/nature20142
[Indexed for MEDLINE]
Free PMC Article

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