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.

Unraveling the Mechanisms of Behaviors Associated With AUDs Using Flies and Worms

“…Evidence that the cellular stress response might be conserved comes from the observation that a Hangover‐related protein, ZNF699, is associated with alcoholism in humans (Riley et al., ). In Drosophila , the Hangover protein is expressed in the nucleus of nearly all neurons and interacts with RNA of the phosphodiesterase 4d (Pde4d) orthologue Dunce (Ruppert et al., ). Identification of the Pde4d orthologue as an interaction partner of Hangover strongly supports the evolutionary conserved nature of the cellular mechanism underlying EtOH tolerance between flies and humans.…”

“…Where does the specificity in the regulation of EtOH‐induced sedation come from and what does this mean for translation to human AUDs? With respect to the rho GTPases and Pde4d orthologue Dunce, the effect of EtOH is isoform‐specific, and distinct isoforms regulate different aspects of acute EtOH intoxication and tolerance (Rothenfluh et al., ; Ruppert et al., ). Comparing functional domains between different isoforms might aid in identification of putative sites within proteins for drug targets.…”

“…At the network level, regulation of EtOH sensitivity and tolerance in flies looks very different than the networks that may regulate EtOH sensitivity and tolerance in humans. In the fly brain, a structure called the central complex exists, and within this structure, specific subsets of neurons are required for EtOH sensitivity and tolerance (Kong et al., ; Ruppert et al., ; Scholz et al., ; Urizar et al., ). EtOH‐induced locomotor activity is regulated by dopamine D1 receptor–expressing neurons in the ellipsoid body, which is part of the central complex (Kong et al., ).…”

“…Neuronal activity of the small field neurons connecting different parts of the central complex is required for the development of tolerance to the effect of EtOH on postural control (Scholz et al., ). The function of the cellular stress protein Hangover can be mapped to 2 F1 neurons that also connect part of the central complex (Ruppert et al., ). The F1 neurons also regulate additional behaviors that involve linking previous motor experience to new information (Ruppert et al., ).…”

“…The function of the cellular stress protein Hangover can be mapped to 2 F1 neurons that also connect part of the central complex (Ruppert et al., ). The F1 neurons also regulate additional behaviors that involve linking previous motor experience to new information (Ruppert et al., ). The general function of the central complex in the fly is to mediate and control higher locomotor behavior (Strauss, ).…”