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., 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, J.S., Yanagisawa, M. (2016). Forward-genetics analysis of sleep in randomly mutagenized mice.  Nature 539(7629): 378--383.

FBrf0235150

Research paper

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.

PMC6076225 (PMC) (EuropePMC)