title: Hangover Links Nuclear RNA Signaling to cAMP Regulation via the Phosphodiesterase 4d Ortholog dunce.
abstract: The hangover gene defines a cellular stress pathway that is required for rapid ethanol tolerance in Drosophila melanogaster. To understand how cellular stress changes neuronal function, we analyzed Hangover function on a cellular and neuronal level. We provide evidence that Hangover acts as a nuclear RNA binding protein and we identified the phosphodiesterase 4d ortholog dunce as a target RNA. We generated a transcript-specific dunce mutant that is impaired not only in ethanol tolerance but also in the cellular stress response. At the neuronal level, Dunce and Hangover are required in the same neuron pair to regulate experience-dependent motor output. Within these neurons, two cyclic AMP (cAMP)-dependent mechanisms balance the degree of tolerance. The balance is achieved by feedback regulation of Hangover and dunce transcript levels. This study provides insight into how nuclear Hangover/RNA signaling is linked to the cytoplasmic regulation of cAMP levels and results in neuronal adaptation and behavioral changes.
authors.affiliation: Department of Biology, Institute for Zoology, Universität zu Köln, 50674 Köln, Germany.
authors.forename: Manuela
authors.initials: M
authors.lastname: Ruppert
authors.affiliation: Institute for Genetics and Neurobiology, University of Würzburg, 97074 Würzburg, Germany.
authors.forename: Mirjam
authors.initials: M
authors.lastname: Franz
authors.affiliation: Institute for Genetics and Neurobiology, University of Würzburg, 97074 Würzburg, Germany.
authors.forename: Anastasios
authors.initials: A
authors.lastname: Saratsis
authors.affiliation: Department of Biology, Institute for Zoology, Universität zu Köln, 50674 Köln, Germany.
authors.forename: Laura
authors.initials: L
authors.lastname: Velo Escarcena
authors.affiliation: Department of Biology, Institute for Zoology, Universität zu Köln, 50674 Köln, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Hendrich
authors.affiliation: Department of Biology, Institute for Zoology, Universität zu Köln, 50674 Köln, Germany.
authors.forename: Li Ming
authors.initials: LM
authors.lastname: Gooi
authors.affiliation: Institute for Genetics and Neurobiology, University of Würzburg, 97074 Würzburg, Germany.
authors.forename: Isabell
authors.initials: I
authors.lastname: Schwenkert
authors.affiliation: Department of Biochemistry, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Ansgar
authors.initials: A
authors.lastname: Klebes
authors.affiliation: Department of Biology, Institute for Zoology, Universität zu Köln, 50674 Köln, Germany; Institute for Genetics and Neurobiology, University of Würzburg, 97074 Würzburg, Germany. Electronic address: henrike.scholz@uni-koeln.de.
authors.forename: Henrike
authors.initials: H
authors.lastname: Scholz
mesh_terms: D000222:Adaptation, Physiological / Q000187:drug effects; D000818:Animals; D001522:Behavior, Animal; D000242:Cyclic AMP / Q000378:metabolism*; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000737:chemistry*; D003593:Cytoplasm / Q000378:metabolism; D029721:Drosophila Proteins / Q000378:metabolism*; D000431:Ethanol / Q000494:pharmacology; D007527:Isoenzymes / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D015138:RNA, Nuclear / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction / Q000187:drug effects; D013347:Subcellular Fractions / Q000187:drug effects / Q000378:metabolism
chemical_list: D029721:Drosophila Proteins; D007527:Isoenzymes; D015138:RNA, Nuclear; C523245:dnc protein, Drosophila; C503359:hang protein, Drosophila; D000431:Ethanol; D000242:Cyclic AMP; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4
keywords: Drosophila melanogaster; Dunce isoforms; PDE4d; alcohol tolerance; cellular stress; dunce; hangover