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; Masashi Yanagisawa

doi:10.1038/nature20142

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 YonezawaSeiya 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, Masashi Yanagisawa

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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.

Original language	English (US)
Pages (from-to)	378-383
Number of pages	6
Journal	Nature
Volume	539
Issue number	7629
DOIs	https://doi.org/10.1038/nature20142
State	Published - 2016

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Funato, H., Miyoshi, C., Fujiyama, T., Kanda, T., Sato, M., Wang, Z., Ma, J., Nakane, S., Tomita, J., Ikkyu, A., Kakizaki, M., Hotta-Hirashima, N., Kanno, S., Komiya, H., Asano, F., Honda, T., Kim, S. J., Harano, K., Muramoto, H., ... Yanagisawa, M. (2016). Forward-genetics analysis of sleep in randomly mutagenized mice. Nature, 539(7629), 378-383. https://doi.org/10.1038/nature20142

Funato, H, Miyoshi, C, Fujiyama, T, Kanda, T, Sato, M, Wang, Z, Ma, J, Nakane, S, Tomita, J, Ikkyu, A, Kakizaki, M, Hotta-Hirashima, N, Kanno, S, Komiya, H, Asano, F, Honda, T, Kim, SJ, Harano, K, Muramoto, H, Yonezawa, T, Mizuno, S, Miyazaki, S, Connor, L, Kumar, V, Miura, I, Suzuki, T, Watanabe, A, Abe, M, Sugiyama, F, Takahashi, S, Sakimura, K, Hayashi, Y, Liu, Q, Kume, K, Wakana, S, Takahashi, JS & Yanagisawa, M 2016, 'Forward-genetics analysis of sleep in randomly mutagenized mice', Nature, vol. 539, no. 7629, pp. 378-383. https://doi.org/10.1038/nature20142

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title = "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.",

author = "Hiromasa Funato and Chika Miyoshi and Tomoyuki Fujiyama and Takeshi Kanda and Makito Sato and Zhiqiang Wang and Jing Ma and Shin Nakane and Jun Tomita and Aya Ikkyu and Miyo Kakizaki and Noriko Hotta-Hirashima and Satomi Kanno and Haruna Komiya and Fuyuki Asano and Takato Honda and Kim, {Staci J.} and Kanako Harano and Hiroki Muramoto and Toshiya Yonezawa and Seiya Mizuno and Shinichi Miyazaki and Linzi Connor and Vivek Kumar and Ikuo Miura and Tomohiro Suzuki and Atsushi Watanabe and Manabu Abe and Fumihiro Sugiyama and Satoru Takahashi and Kenji Sakimura and Yu Hayashi and Qinghua Liu and Kazuhiko Kume and Shigeharu Wakana and Takahashi, {Joseph S} and Masashi Yanagisawa",

note = "Publisher Copyright: {\textcopyright} 2016 Macmillan Publishers Limited.",

year = "2016",

doi = "10.1038/nature20142",

language = "English (US)",

volume = "539",

pages = "378--383",

journal = "Nature",

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T1 - Forward-genetics analysis of sleep in randomly mutagenized mice

AU - Funato, Hiromasa

AU - Miyoshi, Chika

AU - Fujiyama, Tomoyuki

AU - Kanda, Takeshi

AU - Sato, Makito

AU - Wang, Zhiqiang

AU - Ma, Jing

AU - Nakane, Shin

AU - Tomita, Jun

AU - Ikkyu, Aya

AU - Kakizaki, Miyo

AU - Hotta-Hirashima, Noriko

AU - Kanno, Satomi

AU - Komiya, Haruna

AU - Asano, Fuyuki

AU - Honda, Takato

AU - Kim, Staci J.

AU - Harano, Kanako

AU - Muramoto, Hiroki

AU - Yonezawa, Toshiya

AU - Mizuno, Seiya

AU - Miyazaki, Shinichi

AU - Connor, Linzi

AU - Kumar, Vivek

AU - Miura, Ikuo

AU - Suzuki, Tomohiro

AU - Watanabe, Atsushi

AU - Abe, Manabu

AU - Sugiyama, Fumihiro

AU - Takahashi, Satoru

AU - Sakimura, Kenji

AU - Hayashi, Yu

AU - Liu, Qinghua

AU - Kume, Kazuhiko

AU - Wakana, Shigeharu

AU - Takahashi, Joseph S

AU - Yanagisawa, Masashi

PY - 2016

Y1 - 2016

N2 - 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.

AB - 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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U2 - 10.1038/nature20142

DO - 10.1038/nature20142

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AN - SCOPUS:84995918394

SN - 0028-0836

VL - 539

SP - 378

EP - 383

JO - Nature

JF - Nature

IS - 7629

ER -

Forward-genetics analysis of sleep in randomly mutagenized mice

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