UC San Diego

The function of sleep remains a major mystery despite 200 years of research on the subject. Recently, the fruit fly Drosophila has been shown to display a behavior that has the essential characteristics of sleep and has thus become a model for the study of sleep's function. The EGFR/ErbB signaling pathway is well conserved in the central roles it plays in many signaling events during development in worms, flies, and mice. In mammals EGFR/ErbB signaling has also been shown to play a role in circadian regulation of activity. In the current study, its role in the regulation of sleep in Drosophila is examined. The findings reported here show a novel role for Egf-r/ERK signaling in sleep consolidation and maintenance in Drosophila melanogaster. In the adult fruit fly, Egf-r is expressed ubiquitously throughout the nervous system and the current analysis revealed that overexpression of Egf-r pathway signaling components Rho and Star causes an acute, reversible and dose-dependent increase in sleep that tightly parallels an increase in phosphorylated ERK in the head and brain. Inhibition of Egf-r with a dominant-negative form of the receptor was able to suppress the increase in sleep levels produced by Rho and Star, demonstrating that the signal is mediated by the Egf-r pathway. In contrast to the increase in sleep amount after Rho overexpression, inhibiting it lead to a significant decrease in sleep. Importantly, this decrease in sleep was due to a dramatic shortening of the duration of sleep episodes accompanied by an elevation of sleep bout number. This observation suggests a state of increased sleep need, but an inability to maintain the sleep state. Therefore, the function of Rho may be to keep a fly asleep once the state has been initiated. The inhibition of sleep depends on interfering with rhomboid expression in the pars intercerebralis, a part of the fly brain that is functionally analogous to the hypothalamus in vertebrates, which is a region of the mammalian brain well established to be a regulator of arousal. These studies suggest that sleep and its regulation by Egf-r signaling may be ancestral to insects and mammals