RFRPs, a new Family of Hypothalamic Peptides for the Central Control of Female Reproduction – REPRAMIDE

The control of female reproduction has become a major societal and economic concern, and thus a better understanding of the central mechanisms acting on the reproductive axis is necessary. Early studies on the neural pathways involved in the control of the reproductive axis have highlighted the pivotal role of GnRH (Gonadotropin Releasing Hormone) neurons located in the rostral hypothalamus. GnRH release into the portal blood stimulates the secretion of the pituitary gonadotropins which are critical to trigger puberty and to regulate reproductive fonction. In recent years, however, studies have revealed that hypothalamic neurons producing peptides of the RF-amide (Arg-Phe-NH2) family, especially kisspeptins (Kp) and RFamide-related peptide-3 (RFRP-3), play a key role in the control of reproduction. These neuropeptides appear to act upstream of GnRH neurons, and current findings in this domain are leading to a new model for the neuroendocrine control of reproduction.

Kp neurons, located in the arcuate and anteroventral periventricular nuclei, project to GnRH cell bodies and nerve terminals. There, Kp binds to its specific receptor Kiss1R (or GPR54) to potently stimulate GnRH release. Notably, Kp neurons are the main central targets for the positive and negative feedback effects of sex steroids. Moreover, Kp neurons sense metabolic signals to tune reproductive activity according to the energetic status of the organism. In seasonal breeders, Kp expression is regulated by photoperiod and the peptides synchronise reproduction with seasons. Altogether, current data have demonstrated that Kp is a key regulator of the gonadotropic axis in all mammalian species studied so far. On the other hand, RFRP-3, expressed in neurons of the dorsomedial hypothalamus, was first reported to inhibit reproductive activity by reducing GnRH neuron activity and pituitary gonadotropin release. However, recent data report that RFRP-3 activity depends on species, gender and physiological status, indicating complex mechanisms of action. The distribution and pharmacology of the receptor for RFRP-3, GPR147, are poorly known and the lack of selective pharmacological and genetic tools severely limits the study of the RFRP-3/GPR147system. To complicate the picture, a few studies suggest that GPR147 may bind other endogenous RFamide peptides, including Kp.

In this highly competitive context of a renovated understanding of the neuroendocrine control of reproduction in mammals, the main aim of the REPRAMIDE proposal is to elucidate the role and to describe the mechanisms underpinning RFRP-3/GPR147 influence on mammalian reproduction. Our specific objectives are 1) to determine the physiological effect of RFRP-3 on female reproductive activity using three complementary animal models in order to clarify species-specific differences; 2) to generate suitable tools to refine the pharmacological and biochemical knowledge of GPR147; 3) to evaluate the putative interaction between GPR147 and other RF-amide receptors, particularly Kiss1R, both at the pharmacological and physiological levels. The findings obtained in the course of our studies will contribute to the development of better strategies to treat human fertility problem and to manage reproduction in livestock.