Forward-genetics analysis of sleep in randomly mutagenized mice.
Nature 2016 Nov 17; 539(7629):378-383
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. Nature 2016 Nov 17; 539(7629):378-383.
Funato, Hiromasa; Miyoshi, Chika; Fujiyama, Tomoyuki; Kanda, Takeshi; Sato, Makito; Wang, Zhiqiang; Ma, Jing; Nakane, Shin; Tomita, Jun; Ikkyu, Aya; Kakizaki, Miyo; Hotta-Hirashima, Noriko; Kanno, Satomi; Komiya, Haruna; Asano, Fuyuki; Honda, Takato; Kim, Staci J; Harano, Kanako; Muramoto, Hiroki; Yonezawa, Toshiya; Mizuno, Seiya; Miyazaki, Shinichi; Connor, Linzi; Kumar, Vivek; Miura, Ikuo; Suzuki, Tomohiro; Watanabe, Atsushi; Abe, Manabu; Sugiyama, Fumihiro; Takahashi, Satoru; Sakimura, Kenji; Hayashi, Yu; Liu, Qinghua; Kume, Kazuhiko; Wakana, Shigeharu; Takahashi, Joseph S; and Yanagisawa, Masashi, "Forward-genetics analysis of sleep in randomly mutagenized mice." (2016). Faculty Research 2016. 262.