Epidermal growth factor receptor (EGFR) signaling in the mammalian hypothalamus is important in the circadian regulation of activity. We have examined the role of this pathway in the regulation of sleep in Drosophila melanogaster. Our results demonstrate that rhomboid (Rho)- and Star-mediated [ed. note - these are proteases] activation of EGFR and ERK signaling increases sleep in a dose-dependent manner, and that blockade of rhomboid (rho) expression in the nervous system decreases sleep. The requirement of rho for sleep localized to the pars intercerebralis, a part of the fly brain that is developmentally and functionally analogous to the hypothalamus in vertebrates. These results suggest that sleep and its regulation by EGFR signaling may be ancestral to insects and mammals.And a graphic from the review by Colwell:
Proposed role of extracellular signal–regulated kinase (ERK) in the regulation of sleep in Drosophila.
(a) Rho-mediated activation of ERK signaling increases sleep duration. During the night, Rho activation in the pars intercerebralis (PI) leads to the production and secretion of an EGFR ligand. The resulting phosphorylation of EGFR activates ERK in the tritocerebrum (TriC). Although the final targets of this signaling pathway are not known, the phosphorylated ERK seems to stay in the processes of the TriC neurons and may well regulate electrical activity and synaptic transmission in these neurons. (b) During wakefulness, Rho signaling in the PI is proposed to be downregulated, resulting in basal levels of ERK signaling. Inhibition of Rho expression in PI neurons results in decreased sleep levels, with short, fragmented sleep bouts. This observation suggests that these mutant flies have an increased need for sleep but are unable to stay asleep (making them a fly model of insomnia).