Forward-genetics analysis of sleep in randomly mutagenized mice

Nature. 2016 Nov 17;539(7629):378-383. doi: 10.1038/nature20142. Epub 2016 Nov 2.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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

Substances

  • Caenorhabditis elegans Proteins
  • Drosophila Proteins
  • Ion Channels
  • NALCN protein, mouse
  • Nerve Tissue Proteins
  • salt-inducible kinase 3, Drosophila
  • sik3 protein, C elegans
  • Protein-Serine-Threonine Kinases
  • SIK3 protein, mouse