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RFamide-Related Peptide Gene Is a Melatonin-Driven Photoperiodic Gene

Département de Neurobiologie des Rythmes (F.G.R., M.S., P.P., V.S.), Centre National de la Recherche Scientifique Unité Mixte de Recherche-7168/LC2, Institut des Neurosciences Cellulaires et Intégratives, Université Louis Pasteur–Institut Fédératif de Recherche des Neurosciences, 67084 Strasbourg, France; and Department of Translational Neurobiology (F.G.R., J.D.M.), NeuroSearch A/S, Pederstrupvej 93, 2750 Ballerup, Denmark

Address all correspondence and requests for reprints to: Jens D. Mikkelsen, Department of Translational Neurobiology, NeuroSearch A/S, Pederstrupvej 93, 2750 Ballerup, Denmark. E-mail: JDM{at}Neurosearch.dk.

In seasonal species, various physiological processes including reproduction are organized by photoperiod via melatonin, but the mechanisms of melatonin action are still unknown. In birds, the peptide gonadotropin-inhibiting hormone (GnIH) has been shown to have inhibitory effects on reproductive activity and displays seasonal changes of expression. Here we present evidence in mammals that the gene orthologous to GnIH, the RFamide-related peptide (RFRP) gene, expressed in the mediobasal hypothalamus, is strongly regulated by the length of the photoperiod, via melatonin. The level of RFRP mRNA and the number of RFRP-immunoreactive cell bodies were reduced in sexually quiescent Syrian and Siberian hamsters acclimated to short-day photoperiod (SD) compared with sexually active animals maintained under long-day photoperiod (LD). This was contrasted in the laboratory Wistar rat, a non-photoperiodic breeder, in which no evidence for RFRP photoperiodic modulation was seen. In Syrian hamsters, the reduction of RFRP expression in SD was independent from secondary changes in gonadal steroids. By contrast, the photoperiodic variation of RFRP expression was abolished in pinealectomized hamsters, and injections of LD hamsters with melatonin for 60 d provoked inhibition of RFRP expression down to SD levels, indicating that the regulation is dependent on melatonin. Altogether, these results demonstrate that in these hamster species, the RFRP neurons are photoperiodically modulated via a melatonin-dependent process. These observations raise questions on the role of RFRP as a general inhibitor of reproduction and evoke new perspectives for understanding how melatonin controls seasonal processes via hypothalamic targets.

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