Developmental changes in the mammalian gonadotropin-inhibitory hormone (GnIH) ortholog RFamide-related peptide (RFRP) and its cognate receptor GPR147 in the rat hypothalamus

ArticleinInternational journal of developmental neuroscience: the official journal of the International Society for Developmental Neuroscience 30(1):31-7 · October 2011with11 Reads
DOI: 10.1016/j.ijdevneu.2011.10.003 · Source: PubMed
The mammalian gonadotropin-inhibitory hormone (GnIH) ortholog RFamide-related peptide (RFRP) is considered to act on gonadotropin-releasing hormone (GnRH) neurons and on the pituitary to inhibit gonadotropin release and synthesis. To understand the functional significance of this neuropeptide, we investigated the physiological changes in RFRP at mRNA and peptide levels, as well as at the mRNA level of its cognate receptor, G protein-coupled receptor 147 (GPR147), in the rat hypothalamus during development. We also investigated the effects of gonadal steroids on mRNA expression levels of these molecules. In male rats, mRNA expressions of both RFRP and GPR147 increased from postnatal days 12 and 16, peaking at postnatal days 35 and 42, respectively. However, their expressions fell at postnatal day 49. In female rats, mRNA expression of RFRP continued to increase throughout development; mRNA expression of GPR147 in female rats increased from postnatal day 16, peaking at postnatal day 28, but decreased from postnatal day 35. The hypothalamic contents of RFRP on postnatal days 28 and 42 were significantly higher than on postnatal day 4 in male rats, and those on postnatal day 42 were significantly higher than those on postnatal days 4 and 28 in females. Neither orchidectomy nor ovariectomy influenced mRNA expression levels of RFRP or GPR147 in the prepubertal period when endogenous sex steroid levels were low in males and females. Administration of estradiol-17β (E2) increased mRNA expression of RFRP in prepubertal females. These results suggest that the hypothalamic RFRP system changes during development. An ovarian sex steroid, E2, may stimulate mRNA expression of RFRP in the prepubertal period when the basal E2 concentration is low.
    • "Indeed, a portion of RFRP neurons has been shown to co-express ERa in both female Syrian hamsters and rats, indicating a direct effect of E2 on RFRP neurons (Kriegsfeld et al., 2006; Poling et al., 2012; Molnar et al., 2011). In female Syrian hamsters, E2 has been shown to induce c-Fos expression in RFRP neurons (Kriegsfeld et al., 2006), and similarly stimulates Rfrp expression in female rats (Iwasa et al., 2012 ). Based on these findings it is possible that the sex-differences observed in rats and Syrian hamsters, with higher RFRP expression in females than in males (Henningsen et al., 2015; Jorgensen et al., 2014), is driven by an E2-induced stimulation of RFRP expression in females. "
    [Show abstract] [Hide abstract] ABSTRACT: In female mammals, reproduction shows ovarian and daily rhythms ensuring that the timing of the greatest fertility coincides with maximal activity and arousal. The ovarian cycle, which lasts from a few days to a few weeks, depends on the rhythm of follicle maturation and ovarian hormone production, whereas the daily cycle depends on a network of circadian clocks of which the main one is located in the suprachiasmatic nuclei (SCN). In the last ten years, major progress has been made in the understanding of the neuronal mechanisms governing mammalian reproduction with the finding that two hypothalamic Arg-Phe-amide peptides, kisspeptin (Kp) and RFRP, regulate GnRH neurons. In this review we discuss the pivotal role of Kp and RFRP neurons at the interface between the SCN clock signal and GnRH neurons to properly time gonadotropin-induced ovulation. We also report recent findings indicating that these neurons may be part of the multi-oscillatory circadian system that times female fertility. Finally, we will discuss recent investigations indicating a role, and putative therapeutic use, of these neuropeptides in human reproduction.
    Full-text · Article · Jun 2016
    • "In male rats, central administration of RFRP-3 suppresses LH release, but does not affect FSH (Johnson et al., 2007). The expression of RFRP-3 is different at the different developmental stages of sexual maturation (Iwasa et al., 2012 ). RFRP-3 reduces LH release but has no effects on FSH, thyroid hormones and the hormones of the adrenal cortex in male rats (Johnson et al., 2007 ). "
    [Show abstract] [Hide abstract] ABSTRACT: The physiology of reproduction is very complex and is regulated by multiple factors, including a number of hypothalamic neuropeptides. In last few decades, various neuropeptides have been discovered to be involved in stimulation or inhibition of reproduction. In 2000, Tsutsui and colleagues uncovered gonadotropin-inhibitory hormone (GnIH), a neuropeptide generating inhibitory drive to the reproductive axis, in the brain of Coturnix quail. Afterward, GnIH orthologs were discovered in other vertebrates from fish to mammals including human. In these vertebrates, all the discovered GnIH and its ortholgs have LPXRFamide (X = L or Q) sequence at C-terminus. GnIH orthologs of mammals and primates are also termed as RFamide-related peptide (RFRP)-1 and -3 that too have an LPXRFamide (X = L or Q) motif at their C-terminus. GnIH and its orthologs form a member of the RFamide peptide family. GnIH signals via its canonical G protein coupled receptor 147 (GPR147). Both GnIH and GPR147 are expressed in hypothalamus and other brain regions. Besides actions through the hypothalamic GnRH and kisspeptinergic neurons, GnIH-GPR147 signaling exerts inhibitory effect on the reproductive axis via pituitary gonadotropes and directly at gonadal level. Various factors including availability and quality of food, photoperiod, temperature, social interaction, various stresses and some diseases modulate GnIH-GPR147 signaling. In this review, we have discussed expression and actions of GnIH and its orthologs in vertebrates. Special emphasis is given on the role of GnIH-GPR147 signaling pathway in the regulation of reproduction. We have also reviewed and discussed currently available literature on the participation of GnIH-GPR147 signaling pathway in the stress modulation of reproduction.
    Article · May 2016
    • "There are several possible explanations for these observed differences. 17b-estradiol-mediated effects can be highly sensitive to dose and developmental stage, whereby as reported by Iwasa et al. lower estradiol concentrations during the prepubertal stage can cause a stimulatory effect, while higher concentrations during adulthood, a time also marked by decreases in RFRP cell number, result in the suppression of Rfrp mRNA (Iwasa et al., 2012; Poling et al., 2012). Another factor to consider is the existence of heterogeneous subpopulations within RFRP neurons, a common feature in neuropeptidergic systems both in vivo and in vitro (Attardi et al., 1997; Cheng et al., 2010; Dumalska et al., 2008; Goodman et al., 2007). "
    [Show abstract] [Hide abstract] ABSTRACT: A novel RFamide peptide, gonadotropin-inhibitory hormone (GnIH) has emerged as a modulator of avian reproduction. However, the functional role of the mammalian homologue, RFRP-3 remains poorly understood. The RFRP-3 neuronal circuit is influenced by the stress axis. However, whether the Rfrp gene is under direct glucocorticoid (GC)-mediated transcriptional regulation, in the presence and absence of the gonadal steroid, 17β-estradiol, is unknown. We investigated the regulation of the Rfrp (GnIH) and Gpr147 (GnIH-R) transcripts by steroids in a novel hypothalamic Rfrp-expressing cell model, rHypoE-23. The GC agonist, dexamethasone increased Rfrp and Gpr147 mRNA levels. Dexamethasone acted directly on the nuclear GC receptor (GR) to mediate GC-dependent transcriptional changes, independently of de novo protein synthesis. 17β-estradiol had no significant effect on Rfrp or Gpr147 biosynthesis in these neurons. This suggests that Rfrp-expressing neurons serve as potential upstream mediators of stress-induced effects through GR-dependent mechanisms.
    Full-text · Article · Jan 2014
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