Rsu1 regulates ethanol consumption in Drosophila and humans
Friday, 2015/07/31 | 07:43:04
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Shamsideen A. Ojelade, Tianye Jia, Aylin R. Rodan, Tao Chenyang, Julie L. Kadrmas, Anna Cattrell, Barbara Ruggeri, Pimphen Charoeni, Hervé Lemaitre, Tobias Banaschewski, Christian Büchel, Arun L. W. Bokde, Fabiana Carvalho, Patricia J. Conrod, Herta Flor, Vincent Frouin, Jürgen Gallinat, Hugh Garavan, Penny A. Gowland, Andreas Heinz, Bernd Ittermann, Mark Lathrop, Steven Lubbe, Jean-Luc Martinot, Tomás Paus, Michael N. Smolka, Rainer Spanagel, Paul F. O’Reilly, Jaana Laitinen, Juha M. Veijola, Jianfeng Feng, Sylvane Desrivières, Marjo-Riitta Jarvelin, The IMAGEN Consortium, Gunter Schumann, and Adrian Rothenfluh SignificanceGenetic factors play a major role in the development of human addiction. Identifying these genes and understanding their molecular mechanisms are necessary first steps in the development of targeted therapeutic intervention. Here, we have isolated the gene encoding Ras suppressor 1 (Rsu1) in an unbiased genetic screen for altered ethanol responses in the vinegar fly, Drosophila melanogaster. Our behavioral, genetic, and biochemical experiments show that Rsu1 links signaling from the integrin cell adhesion molecule to the small GTPase Rac1 in adult neurons to regulate actin dynamics and alcohol consumption preference. We also show that variants in human RSU1 associate with altered drinking and brain activation during a reward prediction task, thereby validating the predictive power of our approach. AbstractAlcohol abuse is highly prevalent, but little is understood about the molecular causes. Here, we report that Ras suppressor 1 (Rsu1) affects ethanol consumption in flies and humans. Drosophila lacking Rsu1 show reduced sensitivity to ethanol-induced sedation. We show that Rsu1 is required in the adult nervous system for normal sensitivity and that it acts downstream of the integrin cell adhesion molecule and upstream of the Ras-related C3 botulinum toxin substrate 1 (Rac1) GTPase to regulate the actin cytoskeleton. In an ethanol preference assay, global loss of Rsu1 causes high naïve preference. In contrast, flies lacking Rsu1 only in the mushroom bodies of the brain show normal naïve preference but then fail to acquire ethanol preference like normal flies. Rsu1 is, thus, required in distinct neurons to modulate naïve and acquired ethanol preference. In humans, we find that polymorphisms in RSU1 are associated with brain activation in the ventral striatum during reward anticipation in adolescents and alcohol consumption in both adolescents and adults. Together, these data suggest a conserved role for integrin/Rsu1/Rac1/actin signaling in modulating reward-related phenotypes, including ethanol consumption, across phyla.
See: http://www.pnas.org/content/112/30/E4085.abstract.html?etoc PNAS July 28, 2015 vol. 112 no. 30 E4085-E4093
Fig. 1. ics, Encoding Rsu1, is required for normal ethanol responses. Here, flies were exposed to a 130:20 ethanol:airflow rate, and bars represent means ± SEM. ST50 stands for the median sedation time; increased ST50 indicates reduced ethanol sensitivity. (A) Mutant icsG4 flies show reduced sensitivity to ethanol-induced sedation. This phenotype and (Inset) the loss of Rsu1 protein are rescued with expression of Rsu1 cDNA (UAS-Rsu1; transgene presence indicated by √; n = 8). C, control; M, mutant; R, rescue. ***P < 0.001. (B) Brain expression pattern of icsG4 revealed by a membrane-bound GFP reporter (UAS-mCD8-GFP; green). B shows (Upper) anterior (ant.) and (Lower) posterior (post.) confocal stacks of icsG4 (Left) heterozygous WT and (Right) homozygous mutant flies. Expression includes neurosecretory cells in the pars intercerebralis (PI) as well as the MBs. Neuropil is counterstained with anti-Brp nc82 antibody (red).
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