Abstract
Epidermal Growth Factor Receptor (EGFR) signaling has a conserved role in ethanol-induced behavior in flies and mice, affecting ethanol-induced sedation in both species. However it is not known what other effects EGFR signaling may have on ethanol-induced behavior, or what roles other Receptor Tyrosine Kinase (RTK) pathways may play in ethanol induced behaviors. We examined the effects of both the EGFR and Fibroblast Growth Factor Receptor (FGFR) RTK signaling pathways on ethanol-induced enhancement of locomotion, a behavior distinct from sedation that may be associated with the rewarding effects of ethanol. We find that both EGFR and FGFR genes influence ethanol-induced locomotion, though their effects are opposite – EGFR signaling suppresses this behavior, while FGFR signaling promotes it. EGFR signaling affects development of the Drosophila mushroom bodies in conjunction with the JNK MAP kinase basket (bsk), and with the Ste20 kinase tao, and we hypothesize that the EGFR pathway affects ethanol-induced locomotion through its effects on neuronal development. We find, however, that FGFR signaling most likely affects ethanol-induced behavior through a different mechanism, possibly through acute action in adult neurons.
Highlights
Though alcohol dependence is highly influenced by genetics, it has proven difficult to conclusively identify genes that confer risk or that could be targets for therapy [1,2,3]
Locomotion Because of previous evidence suggesting an interaction between tao and Receptor Tyrosine Kinase (RTK) signaling genes in Drosophila [34], we investigated whether RTK genes might affect ethanol-induced locomotor stimulation
We found that flies heterozygous for an Egfr null allele (Egfrf24/+) showed increased ethanol-induced locomotion (Fig. 2A,C), and that a hypomorphic mutation in rhomboid, a protease required for Epidermal Growth Factor Receptor (EGFR) ligand processing (Fig. 1A) [36], increased ethanol-induced locomotion (Fig. 2B,C)
Summary
Though alcohol dependence is highly influenced by genetics, it has proven difficult to conclusively identify genes that confer risk or that could be targets for therapy [1,2,3]. Because genes controlling neuronal development and function are well conserved between Drosophila and mammals, and because flies exhibit a number of ethanol-induced behaviors that are analogous to mammalian behaviors, Drosophila has been used successfully to identify genetic pathways affecting ethanol-induced behaviors that have conserved roles in mammalian systems [9,10,11,12]. Ethanol has both stimulant and sedative effects in Drosophila [4,13]. In Drosophila, as in mammals, doses of ethanol that induce increased locomotor activity are associated with the rewarding effects of intoxication [6,15]
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