For an activity in which we spend about a third of our lifetime, much about sleep remains enigmatic. Foltenyi et al. investigated the role of epidermal growth factor receptor (EGFR) signaling in regulating sleep in Drosophila melanogaster. Activation of fly EGFR ligands like Spitz depends on the transmembrane protein Star and on Rhomboid family (Rho) proteases. Using flies in which Rho and Star expression could be conditionally induced, the authors showed that their overexpression led to a dose-dependent increase in sleep. There was a transient increase in both the duration and number of sleep episodes, which was followed by a decrease and then a return to normal. Overexpression of a soluble form of Spitz, which does not require Rho processing, had similar effects. Overexpression of Rho and Star led to an increase in phosphorylation of extracellular signal-regulated kinase (ERK, a target of EGFR signaling) in the head that paralleled the temporal pattern of increased sleep, an increase that was blocked by coexpression of a dominant-negative EGFR mutant. Immunohistochemical analysis indicated that the increase in ERK phosphorylation was greatest in the tritocerebrum. Moreover, several lines of flies in which Rho activity in neurons projecting from the pars intercerebralis (PI, a region analogous to the vertebrate hypothalamus) to the tritocerebrum was inhibited with RNAi showed decreased sleep. This decrease involved brief sleep episodes in conjunction with an increase in the number of times that sleep was attempted--a pattern that could constitute a fly model of insomnia. The authors propose that the production of EGFR ligand by PI neurons leads to ERK activation in tritocerebrum neurons, thereby promoting sleep. Colwell provides thoughtful commentary.
K. Foltenyi, R. J. Greenspan, J. W. Newport, Activation of EGFR and ERK by rhomboid signaling regulates the consolidation and maintenance of sleep in Drosophila. Nat. Neurosci. 10, 1160-1167 (2007). [PubMed]
C. S. Colwell, Soporific signaling: How flies sleep through the night. Nat. Neurosci. 10, 1079-1080 (2007). [PubMed]