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Forward-genetics analysis of sleep in randomly mutagenized mice.


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.

SUBMITTER: Funato H 

PROVIDER: S-EPMC6076225 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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Forward-genetics analysis of sleep in randomly mutagenized mice.

Funato Hiromasa H   Miyoshi Chika C   Fujiyama Tomoyuki T   Kanda Takeshi T   Sato Makito M   Wang Zhiqiang Z   Ma Jing J   Nakane Shin S   Tomita Jun J   Ikkyu Aya A   Kakizaki Miyo M   Hotta-Hirashima Noriko N   Kanno Satomi S   Komiya Haruna H   Asano Fuyuki F   Honda Takato T   Kim Staci J SJ   Harano Kanako K   Muramoto Hiroki H   Yonezawa Toshiya T   Mizuno Seiya S   Miyazaki Shinichi S   Connor Linzi L   Kumar Vivek V   Miura Ikuo I   Suzuki Tomohiro T   Watanabe Atsushi A   Abe Manabu M   Sugiyama Fumihiro F   Takahashi Satoru S   Sakimura Kenji K   Hayashi Yu Y   Liu Qinghua Q   Kume Kazuhiko K   Wakana Shigeharu S   Takahashi Joseph S JS   Yanagisawa Masashi M  

Nature 20161102 7629


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 ti  ...[more]

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