Editors' ChoiceNeuroscience

Sleep cyclin

Sci. Signal.  07 Jul 2015:
Vol. 8, Issue 384, pp. ec183
DOI: 10.1126/scisignal.aac9397

Despite great differences in brain architecture, several genes implicated in mammalian sleep also regulate sleep in the fruit fly Drosophila melanogaster. Afonso et al. identified mutations in taranis (tara) that reduced both the number and duration of sleep bouts in adult flies in a manner that was independent of the circadian clock and light-dark cycle. Tara was present in most neurons of the brain, and removing Tara function specifically in cholinergic neurons disrupted sleep. Tara is a transcriptional cofactor of the Trip-Br family, also known as the SERTAD [SERTA (SEI-1, RBT1, and TARA) domain] family, that regulates cell cycle progression and contains a Cyclin A (CycA) binding motif. Tagged versions of Tara and CycA coimmunoprecipitated from extracts of cultured S2 cells. Flies heterozygous for a null allele of CycA showed a mild reduction in total daily sleep, and heterozygosity for a weak loss-of-function allele of CycA enhanced the reduced sleep phenotype of tara mutants. CycA was present in a subset of neurons of the pars lateralis, a region of the fly brain that contains neurosecretory cells and may be analogous to the mammalian hypothalamus. Compared with controls, the abundance of CycA in both cell bodies and synapses in these cells was reduced in tara mutants. However, there was no change in the abundance of CycA transcripts, implying that Tara affected the abundance of CycA through a nontranscriptional mechanism. Flies that expressed either a sodium channel that stimulates neuronal activity or a tara RNAi construct specifically in the pars lateralis slept less. CycA may either inhibit or stimulate the activity of Cyclin-dependent kinase 1 (Cdk1) depending on the context. Experiments using overexpression of wild-type Cdk1 and a form that cannot be inhibited indicated that Cdk1 reduced sleep. Heterozygosity for a loss-of-function mutation in Cdk1 did not affect sleep, but partially rescued the reduced sleep phenotypes of tara mutants and of flies heterozygous for a null allele of CycA. These results suggest that CycA is a central regulator of sleep cycles and inhibits Cdk1 activity in this context. Whereas Cdk1 activity promotes wakefulness, Tara promotes sleep by increasing the abundance of CycA, which inhibits Cdk1 activity.

D. J. S. Afonso, D. Liu, D. R. Machado, H. Pan, J. E. C. Jepson, D. Rogulja, K. Koh, TARANIS functions with Cyclin A and Cdk1 in a novel arousal center to control sleep in Drosophila. Curr. Biol. 25, 1717–1726 (2015). [PubMed]