Forward-genetics analysis of sleep in randomly mutagenized mice

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

Hiromasa Funato ¹ ², Chika Miyoshi ¹, Tomoyuki Fujiyama ¹, Takeshi Kanda ¹, Makito Sato ¹ ³, Zhiqiang Wang ¹, Jing Ma ¹, Shin Nakane ⁴, Jun Tomita ⁴, Aya Ikkyu ¹, Miyo Kakizaki ¹, Noriko Hotta-Hirashima ¹, Satomi Kanno ¹, Haruna Komiya ¹, Fuyuki Asano ¹, Takato Honda ¹, Staci J Kim ¹, Kanako Harano ¹, Hiroki Muramoto ¹, Toshiya Yonezawa ¹, Seiya Mizuno ⁵, Shinichi Miyazaki ¹, Linzi Connor ¹, Vivek Kumar ⁶ ⁷, Ikuo Miura ⁸, Tomohiro Suzuki ⁸, Atsushi Watanabe ⁹, Manabu Abe ¹⁰, Fumihiro Sugiyama ⁵, Satoru Takahashi ⁵, Kenji Sakimura ¹⁰, Yu Hayashi ¹ ¹¹, Qinghua Liu ¹ ¹², Kazuhiko Kume ⁴, Shigeharu Wakana ⁸, Joseph S Takahashi ¹ ⁶ ¹³, Masashi Yanagisawa ¹ ³ ¹³ ¹⁴

Affiliations

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.

PMID: 27806374 DOI: 10.1038/nature20142

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.

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