Ruppert Manuela, Franz Mirjam, Saratsis Anastasios, Velo Escarcena Laura, Hendrich Oliver, Gooi Li Ming, Schwenkert Isabell, Klebes Ansgar, Scholz Henrike
Department of Biology, Institute for Zoology, Universität zu Köln, 50674 Köln, Germany.
Institute for Genetics and Neurobiology, University of Würzburg, 97074 Würzburg, Germany.
Cell Rep. 2017 Jan 10;18(2):533-544. doi: 10.1016/j.celrep.2016.12.048.
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.
宿醉基因定义了一种细胞应激途径，该途径是果蝇快速产生乙醇耐受性所必需的。为了了解细胞应激如何改变神经元功能，我们在细胞和神经元水平上分析了宿醉基因的功能。我们提供的证据表明，宿醉基因作为一种核RNA结合蛋白发挥作用，并且我们鉴定出磷酸二酯酶4d的直系同源基因迟钝基因作为靶RNA。我们构建了一个转录本特异性的迟钝基因突变体，该突变体不仅在乙醇耐受性方面受损，而且在细胞应激反应中也受损。在神经元水平上，迟钝基因和宿醉基因在同一对神经元中发挥作用，以调节依赖于经验的运动输出。在这些神经元内，两种环磷酸腺苷（cAMP）依赖性机制平衡了耐受程度。这种平衡是通过对宿醉基因和迟钝基因转录本水平的反馈调节来实现的。这项研究深入揭示了核宿醉基因/RNA信号传导如何与cAMP水平的细胞质调节相联系，并导致神经元适应和行为变化。
