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.