Hangover Links Nuclear RNA Signaling to cAMP Regulation via the Phosphodiesterase 4d Ortholog dunce

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. [Display omitted] •The nuclear stress protein Hangover binds RNA.•The Pde4d ortholog dunce is a target of Hangover signaling.•Both mediate experience-dependent behavioral changes in the same neurons.•Hangover links two cAMP-dependent mechanisms to regulate ethanol tolerance. Cellular stressors like ethanol cause specific behavioral changes. Ruppert et al. show that the nuclear stress RNA-interacting protein Hangover is broadly expressed but only required in neurons mediating experience-dependent changes in behavior. At the cellular level, Hangover links nuclear signaling to cAMP regulation via the phosphodiesterase 4d ortholog Dunce.