Image reprinted from Nature Neuroscience.
Many insomniacs dream of a good night's sleep. Although the pharmaceutical industry markets several sleep aids, millions of people still have trouble falling asleep or staying asleep. What are the molecular mechanisms of sleep? Foltenyi et al. report that epidermal growth factor receptor (EGFR) signaling regulates sleep in Drosophila in a recent article in Nature Neuroscience.
Drosophila show behavior consistent with sleep in mammals. Drosophila are inactive for long periods of time during which they are difficult to arouse. Drosophila sleep more following sleep deprivation, consistent with 'sleep rebound' in mammals. Drugs that prevent sleep in mammals, including caffeine and amphetamines, have the same effect in Drosophila.
In mammals, the suprachiasmatic nucleus secretes the EGFR ligand transforming growth factor-
(TGF-). In Drosophila, the three TGF- homologs, Spitz, Gurken and Keren, are processed by proteases, Star and members of the rhomboid family, that cleave the membrane-bound EGFR ligands into their active forms.
The authors generated Drosophila expressing both rhomboid-1 (rho) and Star under the control of the heat shock promoter. Heat shock increased sleep duration during both day, when Drosophila are normally awake, and night, when they are normally asleep. Drosophila overexpressing rho and Star showed increases in both the number and length of sleep bouts. However, a dominant negative form of EGFR blocked the sleep increase in these Drosophila. Heat shock increased phosphorylation of extracellular signal-regulated kinase (ERK) in Drosophila expressing heat-shock activated rho and Star but not in Drosophila co-expressing dominant negative EGFR, consistent with Rho- and Star-mediated regulation of EGFR signaling.
Is EGFR activation necessary for sleep? Researchers previously designed a mutant rho expression vector (rhoDN) that reduces endogenous Rho expression by RNA interference. The authors drove rhoDN expression with 48 different promoters that induce restricted neural expression patterns and found 4 Drosophila lines with reduced sleep. In these Drosophila lines, each bout of sleep was shorter, but the total number of sleep bouts was greater relative to control Drosophila. These data suggest that Drosophila with disruptions in EGFR signaling try to sleep, but cannot stay asleep, consistent with people with insomnia. Soluble Spitz increased sleep in Drosophila expressing rhoDN, consistent with the specific involvement of EGFR in sleep.
Where is the sleep center in the Drosophila brain? Like the hypothalamus, which helps control sleep in mammals, the Drosophila pars intercerebralis (PI) contains neurosecretory cells. Endogenous Rho and the rhoDN drivers that reduced sleep localized to PI, suggesting that this region governs the secretion of EGFR ligands. PI neurons project to the tritocerebrum. In Drosophila expressing exogenous rho and Star, phosphorylated ERK localized to the tritocerebrum, suggesting that EGFR localizes there.
Disrupting EGFR signaling affected the amount of sleep, but not its timing. Drosophila expressing rhoDN showed circadian rhythms with normal period and phase. Therefore, region-specific EGFR regulation may help people with insomnia get more sleep without disrupting daily routines.