UC San Diego

Gonadotropin-releasing hormone (GnRH) secretion from the brain regulates reproductive function through its stimulation of the anterior pituitary and the subsequent release of gonadotropins and their stimulation of the gonads. RFamide-related peptide 3 (RFRP-3, gene name Rfrp) is known to be a potent suppressor of GnRH and gonadotropin secretion in adult rodents, but the role of this neuropeptide in normal reproductive function and the regulation of this peptide remain unclear. RFRP-3 was discovered as the mammalian ortholog of the avian gonadotropin-inhibitory hormone; however, the role and importance of RFRP-3 in mammalian reproduction remains equivocal. The work presented herein investigates the role of RFRP-3 in various perturbations of the reproductive axis in mice in an effort to pinpoint where RFRP-3 fits into the greater network of reproductive control. First, general characterization of RFRP-3's effects on various hormones and neuropeptide systems were assayed demonstrating a potent suppression of luteinizing hormone secretion. Interconnections of the RFRP-3 and kisspeptin systems were also examined, and while RFRP-3 may regulate the kisspeptin neuronal network, this connection was found to not be reciprocal. Next, steroidal suppressive regulation of RFRP-3 neurons by estrogens and androgens was quantified, as well as changes in Rfrp expression in a model of the preovulatory LH surge. RFRP-3 was also examined in the context of stress, both metabolic and immobilization, which induced changes in the expression and activation of Rfrp neurons. Lastly, RFRP-3 neurons were investigated during development where drastic changes in Rfrp expression were found to occur. Collectively, these data provide a near exhaustive survey of the role of RFRP-3 in mouse reproduction