Forward-genetics analysis of sleep in randomly mutagenized mice

Hiromasa Funato (), Chika Miyoshi, Tomoyuki Fujiyama, Takeshi Kanda, Makito Sato, Zhiqiang Wang, Jing Ma, Shin Nakane, Jun Tomita, Aya Ikkyu, Miyo Kakizaki, Noriko Hotta-Hirashima, Satomi Kanno, Haruna Komiya, Fuyuki Asano, Takato Honda, Staci J. Kim, Kanako Harano, Hiroki Muramoto, Toshiya Yonezawa, Seiya Mizuno, Shinichi Miyazaki, Linzi Connor, Vivek Kumar, Ikuo Miura, Tomohiro Suzuki, Atsushi Watanabe, Manabu Abe, Fumihiro Sugiyama, Satoru Takahashi, Kenji Sakimura, Yu Hayashi, Qinghua Liu, Kazuhiko Kume, Shigeharu Wakana, Joseph S. Takahashi () and Masashi Yanagisawa ()
Additional contact information
Hiromasa Funato: International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba
Chika Miyoshi: International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba
Tomoyuki Fujiyama: International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba
Takeshi Kanda: International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba
Makito Sato: International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba
Zhiqiang Wang: International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba
Jing Ma: International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba
Shin Nakane: Graduate School of Pharmaceutical Sciences, Nagoya City University
Jun Tomita: Graduate School of Pharmaceutical Sciences, Nagoya City University
Aya Ikkyu: International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba
Miyo Kakizaki: International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba
Noriko Hotta-Hirashima: International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba
Satomi Kanno: International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba
Haruna Komiya: International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba
Fuyuki Asano: International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba
Takato Honda: International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba
Staci J. Kim: International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba
Kanako Harano: International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba
Hiroki Muramoto: International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba
Toshiya Yonezawa: International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba
Seiya Mizuno: Laboratory Animal Resource Center, University of Tsukuba
Shinichi Miyazaki: International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba
Linzi Connor: International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba
Vivek Kumar: University of Texas Southwestern Medical Center
Ikuo Miura: Technology and Development Team for Mouse Phenotype Analysis, RIKEN Bioresource Center
Tomohiro Suzuki: Technology and Development Team for Mouse Phenotype Analysis, RIKEN Bioresource Center
Atsushi Watanabe: Laboratory of Research Advancement, National Center for Geriatrics and Gerontology
Manabu Abe: Brain Research Institute, Niigata University
Fumihiro Sugiyama: Laboratory Animal Resource Center, University of Tsukuba
Satoru Takahashi: Laboratory Animal Resource Center, University of Tsukuba
Kenji Sakimura: Brain Research Institute, Niigata University
Yu Hayashi: International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba
Qinghua Liu: International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba
Kazuhiko Kume: Graduate School of Pharmaceutical Sciences, Nagoya City University
Shigeharu Wakana: Technology and Development Team for Mouse Phenotype Analysis, RIKEN Bioresource Center
Joseph S. Takahashi: International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba
Masashi Yanagisawa: International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba

Nature, 2016, vol. 539, issue 7629, 378-383

Abstract: 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.

Date: 2016
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DOI: 10.1038/nature20142

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