Journal Article

Forward-genetics analysis of sleep in randomly mutagenized mice

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

2016

نظرة عامة

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. Two mutations affecting the sleep–wakefulness balance in mice are detected, showing that the SIK3 protein kinase is essential for determining daily wake time, and the NALCN cation channel regulates the duration of rapid eye movement sleep. Genes controlling sleep patterns Although the molecular pathways regulating circadian rhythms have been extensively explored and catalogued, much less is known about the molecular mechanisms controlling and driving sleep homeostasis. Using a forward genetic screen, Hiromasa Funato et al . identify two mutations affecting sleep/wakefulness balance. The Sik3 protein kinase was shown to be essential for determining total wake time, and mutations in the cation channel NALCN modulated REM sleep episode duration and total REM sleep time.

• الناشر: Nature Publishing Group UK,Nature Publishing Group
• موضوع: 631/208/1515 / 631/378/1385/2641 / 631/378/1385/519 / Amino Acid Sequence / Animals / Caenorhabditis elegans - genetics / Caenorhabditis elegans Proteins - chemistry / Caenorhabditis elegans Proteins - genetics / Caenorhabditis elegans Proteins - metabolism / Conserved Sequence / Drosophila melanogaster - genetics / Drosophila Proteins - chemistry / Drosophila Proteins - genetics / Drosophila Proteins - metabolism / Electroencephalography / Electromyography / Genetic aspects / Genetic testing / Genetics / Genotype & phenotype / Homeostasis - genetics / Humanities and Social Sciences / Ion Channels - chemistry / Ion Channels - genetics / Ion Channels - metabolism / Kinases / Membrane Proteins / Methods / Mice / multidisciplinary / Mutagenesis / Mutation / Nerve Tissue Proteins - chemistry / Nerve Tissue Proteins - genetics / Nerve Tissue Proteins - metabolism / Neurons - metabolism / Phosphorylation / Physiological research / Protein Serine-Threonine Kinases - chemistry / Protein Serine-Threonine Kinases - genetics / Protein Serine-Threonine Kinases - metabolism / Proteins / Random Allocation / Rapid eye movement / RNA Splicing - genetics / Rodents / Science / Sleep / Sleep - genetics / Sleep - physiology / Sleep Deprivation / Sleep, REM - genetics / Sleep, REM - physiology / Time Factors / Wakefulness - genetics / Wakefulness - physiology