Sleep is still an enigmatic phenomenon, mainly because we do not know its precise function and regulation. At least we know that it is essential to our physical and mental health. If we don't get enough, our performance really suffers. The need for sleep varies from person to person and it seems that this has a genetic basis. Identifying genes that affect sleep duration could therefore help us to understand the underlying principles. In a recent article published in Science, Amita Sehgal and her team from the University of Pennsylvania report on a gene whose loss of function renders fruit flies sleepless.

In contrast to the common view, sleep is not unique to vertebrates. At the turn of the millennium it became pretty clear that it also occurs in invertebrates, suggesting that sleep fulfils some really fundamental functions. Also, Drosophila fruit flies, which are easy to manipulate genetically, experience periods of sleep-like states. Therefore, Amita Sehgal's team dug in their bag of genetic tricks to dissect the sleep phenomenon in these animals. To identify genes involved in sleep regulation,they screened thousands of mutant fly lines for animals exhibiting a reduction in daily sleep. Eventually, they obtained a mutant with an extreme reduction in sleep caused by the functional loss of a gene that they named sleepless. The gene encodes a membrane-anchored, glycosylated protein that is significantly enriched in the brain of the flies.

The scientists were careful not to jump to conclusions. They knew that they first had to ensure that sleepless is really responsible for the observed phenotype. As the mutation was the result of the insertion of a transposon into the sleepless gene, they excised the transposon from the gene to see if its removal restored the daily sleep pattern. Indeed, after doing so the flies slept normally again. Additionally, they re-introduced the wild-type gene into the sleepless mutant insects, and this also rescued the sleep deficiency. These and further experiments indicated that sleepless is truly required for sleep in Drosophila.

Sleep is controlled by circadian and homeostatic mechanisms. While the circadian clock regulates the timing of sleep, the homeostatic process controls the need for sleep, which – as we all know – increases with length of sleep deprivation. Therefore the team tested whether sleepless affects circadian or homeostatic sleep control. Because it is difficult to deprive the already sleep-deprived sleepless flies further, the team used other mutant flies, which show less sleep reduction due to incomplete disruption of the sleepless gene, to discover whether sleepless regulates homeostatic or circadian sleep mechanisms. The finding that these flies showed a significant reduction in rebound sleep,which allows animals to recover from sleep deprivation, but that sleep under normal conditions was minimally affected, suggests that sleeplessimpairs homeostatic sleep control.

A previous study provided exciting evidence that a Shaker-type potassium channel may regulate the need for sleep by affecting neuronal excitability. But how does the sleepless gene exert its effects on sleep? A potential mechanism by which sleepless controls sleep is suggested by the team's finding that the previously described quiver mutant, which contains a mutation known to affect Shaker-dependent potassium currents, is one form of the sleepless gene found in fly populations. Thus, is seems that the sleepless protein may convey a signal that connects sleep drive to lowered neuronal excitability. Validating this idea will require more experimental efforts and will certainly cause many additional sleepless nights for both scientists and fruit flies.

Koh, K., Joiner, W. J., Wu, M. N., Yue, Z., Smith, C. J. and Sehgal, A. (
). Identification of SLEEPLESS, a Sleep-Promoting Factor.