RFamide-related peptide-3 (RFRP-3) suppresses sexual maturation in a eusocial mammal

Abstract

Neuroendocrine mechanisms underlying social inhibition of puberty are not well understood. Here, we use a model exhibiting the most profound case of pubertal suppression among mammals to explore a role for RFamide-related peptide-3 [RFRP-3; mammalian ortholog to gonadotropin-inhibitory hormone (GnIH)] in neuroendocrine control of reproductive development. Naked mole rats (NMRs) live in sizable colonies where breeding is monopolized by two to four dominant animals, and no other members exhibit signs of puberty throughout their lives unless they are removed from the colony. Because of its inhibitory action on the reproductive axis in other vertebrates, we investigated the role of RFRP-3 in social reproductive suppression in NMRs. We report that RFRP-3 immunofluorescence expression patterns and RFRP-3/GnRH cross-talk are largely conserved in the NMR brain, with the exception of the unique presence of RFRP-3 cell bodies in the arcuate nucleus (Arc). Immunofluorescence comparisons revealed that central expression of RFRP-3 is altered by reproductive status, with RFRP-3 immunoreactivity enhanced in the paraventricular nucleus, dorsomedial nucleus, and Arc of reproductively quiescent NMRs. We further observed that exogenous RFRP-3 suppresses gonadal steroidogenesis and mating behavior in NMRs given the opportunity to undergo puberty. Together, our findings establish a role for RFRP-3 in preserving reproductive immaturity, and challenge the view that stimulatory peptides are the ultimate gatekeepers of puberty.eusocial | GnIH | naked mole rat | puberty | RFRP-3

Gonadotrophin‐inhibitory hormone and its mammalian orthologue RFamide‐related peptide‐3: Discovery and functional implications for reproduction and stress

“…RFRP‐3 administration also alters cellular activity in key neural loci implicated in female reproductive behaviour, including the medial preoptic area, medial amygdala and bed nucleus of the stria terminalis, independent of changes in circulating gonadal steroids . These results are consistent with additional reports of GnIH/RFRP‐3 induced inhibition of sexual behaviour in avian and rodent species . Taken together, these data point to a neuromodulatory role for RFRP‐3 in female sexual motivation, independent of downstream alterations in sex steroid production.…”

“…As indicated previously, the first evidence of a direct interaction of GnIH and GnRH in the brain came from a neuroanatomical study on birds . Putative contacts by GnIH/RFRP‐3 cells onto GnRH cells in the hypothalamus have subsqeuently been demonstrated in all vertebrates studied, including fish, frogs, hamsters, mice, rats, sheep, monkeys, naked mole‐rats and humans . Although there is putative contact between GnIH/RFRP‐3 and GnRH cells in all vertebrates studied, a functional interaction remains to be demonstrated in some cases.…”

“…15 Putative contacts by GnIH/RFRP-3 cells onto GnRH cells in the hypothalamus have subsqeuently been demonstrated in all vertebrates studied, including fish, frogs, hamsters, mice, rats, sheep, monkeys, naked mole-rats and humans. 30,36,44,45,[47][48][49] Although there is putative contact between GnIH/RFRP-3 and GnRH cells in all vertebrates studied, a functional interaction remains to be demonstrated in some cases. However, in birds and mammals, GnRH neurones express GPR147.…”

Gonadotropin-Inhibitory Hormone Plays Roles in Stress-Induced Reproductive Dysfunction

“…These data indicate that hypothalamic GnIH/RFRP-3 integrates the suppressive effects of glucocorticoid on the HPG axis under psychological stress conditions. Recently, Peragine et al showed that RFRP-3 suppresses sexual maturation in socially non-dominant female rats living in colonies, where breeding is monopolized by dominant animals (35). This result also indicates that RFRP-3 may be involved in the social stress-induced suppression of reproductive function.…”

The roles of kisspeptin and gonadotropin inhibitory hormone in stress-induced reproductive disorders

“…These findings suggest that GnIH/RFRP-3 mediates the suppressive effects of glucocorticoids on the HPG axis under stress conditions. Interestingly, a recent study has shown that GnIH/RFRP-3 suppressed sexual maturation in socially non-dominant female rats living in colonies, indicating that GnIH/RFRP-3 is related to social stressinduced reproductive disorders [88]. As has been found for kisspeptin, relatively severe stress protocols are needed to affect the hypothalamic GnIH/RFRP-3 system; e.g., high-dose LPS (2-5 mg/kg) was used to evaluate the effects of immune stress [81,89], and a repeated immobilization protocol was used to evaluate the effects of psychological stress [83].…”