RRC ID 47237
Author 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.
Title Forward-genetics analysis of sleep in randomly mutagenized mice.
Journal Nature
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.
Volume 539(7629)
Pages 378-383
Published 2016-11-17
DOI 10.1038/nature20142
PII nature20142
PMID 27806374
PMC PMC6076225
MeSH Amino Acid Sequence Animals Caenorhabditis elegans / genetics Caenorhabditis elegans Proteins / chemistry Caenorhabditis elegans Proteins / genetics Caenorhabditis elegans Proteins / metabolism Conserved Sequence Drosophila Proteins / chemistry Drosophila Proteins / genetics Drosophila Proteins / metabolism Drosophila melanogaster / genetics Electroencephalography Electromyography Homeostasis / genetics Ion Channels / chemistry Ion Channels / genetics* Ion Channels / metabolism Mice Mutagenesis* Mutation* Nerve Tissue Proteins / chemistry Nerve Tissue Proteins / genetics* Nerve Tissue Proteins / metabolism Neurons / metabolism Phosphorylation Protein-Serine-Threonine Kinases / chemistry Protein-Serine-Threonine Kinases / genetics* Protein-Serine-Threonine Kinases / metabolism RNA Splicing / genetics Random Allocation Sleep / genetics* Sleep / physiology* Sleep Deprivation Sleep, REM / genetics Sleep, REM / physiology Time Factors Wakefulness / genetics Wakefulness / physiology
IF 43.07
Times Cited 9
Human and Animal Cells 293(RCB1637) 293T(RCB2202)