hangover links nuclear RNA signalling to cAMP regulation via phosphodiesterase 4d orthologe dunce

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Manuela Ruppert1, Mirjam Franz2, Anastasios Saratsis2, Laura Velo-Escarcena1, Oliver Hendrich1, Li Ming Gooi1, Isabell Schwenkert1, Ansgar Klebes3 and Henrike Scholz1,2
1Universität zu Köln, Animal Physiology, 50674 Köln, Germany
2University of Würzburg, Am Hubland, 97074 Würzburg, Germany
3UCSF, Department of Biochemistry, Parnassus Ave. 513, 94143 San Francisco, USA
We established Drosophila melanogaster as a suitable model system to study ethanol tolerance and ethanol induced mechanistically similar to human behaviors associated with alcohol abuse disorders (Scholz et al., 2000; Neuron: 28, 261-271). Previously, we shown that the hangover gene (hang) of Drosophila melanogaster defines a stress pathway required for ethanol tolerance (Scholz et al., 2005; Nature 436, 845-847). In humans is the Hang related protein – ZNF699 – associated with alcoholism (Riley et al., 2006; Mol Psychiatry 11, 1025-1031) supporting the idea that a cellular stress mechanism underlying ethanol tolerance is evolutionary conserved between humans and flies. However up to now it is still not clear how broadly increases of cellular stressors like ethanol changes behaviors specifically.
To understand how cellular stress changes neuronal function, we investigated Hangover function on a cellular and network level. We performed expression studies and biochemical analyses. We show that Hangover is a nuclear protein that can bind RNA. Transcriptome analysis revealed that the phosphodiesterase 4d orthologue dunce is a putative target Hangover signaling. Our newly generated isoform specific dunce mutants share with hangover mutants a similar reduced tolerance phenotype, cellular stress defects and altered cAMP levels. Behavioral studies combined with neuroanatomical analysis revealed that both genes are required in the same pair of neurons mediating experience dependent changes of behavior. Furthermore we show that not the complete amount of cAMP within a cell regulates the amount of tolerance formed, rather two cAMP dependent mechanisms that regulate each other. Both mechanisms are linked by the nuclear Hangover protein with each other. This study provides new mechanistic insight into how cellular stressors like ethanol changes behaviors specifically. Funded by DFG 656/7-2, DFG 656/5-1 and BMBF “SysMedAlcoholism to H.S.