Temporal phase relation of circadian neural oscillations alters RFamide-related peptide-3 and testicular function in the mouse.
TL;DR: Findings not only suggest the modulation of gonadal development in mice by changing the temporal phase relation of serotonergic and dopaminergic oscillations, but also demonstrate an inverse correlation of RFRP-3 neurons and gonadal activity in both control and experimental conditions.
Abstract: In order to study the effect of the temporal synergism of neural oscillations on reproductive regulation and the response of RFamide-related peptide-3 (RFRP-3; a mammalian ortholog of avian gonadotropin-inhibitory hormone), expression of immunoreactive RFRP-3 in the neurons of the dorsomedial nucleus of the hypothalamus was monitored in sexually immature and mature laboratory mice (study I). In study II, the effects of serotonin and dopamine precursors (5-hydroxytryptophan and L-dihydroxyphenylalanine; injected daily, 8 or 12 h apart, for 13 days in 3-week-old mice) on testicular activity and immunoreactive RFRP-3 neurons were studied until 24 days after treatment. Results indicate high levels of expression of immunoreactive RFRP-3 in the sexually immature and 8-hour mice (simulating gonadal suppression), while a low level was noted in mature and 12-hour mice (simulating gonadal stimulation). These findings not only suggest the modulation of gonadal development in mice (during the course of puberty attainment) by changing the temporal phase relation of serotonergic and dopaminergic oscillations (as in some seasonally breeding species), but also demonstrate an inverse correlation of RFRP-3 neurons and gonadal activity in both control and experimental conditions.
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TL;DR: Interestingly, two interspersed subpopulations of Rfrp cells are identified, which have unique developmental and steroidal regulation characteristics and the number of LE cells robustly decreases during postnatal development, whereas HE cell number increases significantly before puberty.
Abstract: Arginine-phenylalanine-amide (RFamide)-related peptide 3 (RFRP-3, encoded by the Rfrp gene) is the mammalian ortholog of gonadotropin-inhibiting hormone and can inhibit GnRH neuronal activity and LH release. However, the development and regulation of the RFRP-3 system in both sexes is poorly understood. Using in situ hybridization, we examined changes in Rfrp-expressing neurons in mice of both sexes during development and under different adulthood hormonal milieus. We found no sex differences in Rfrp expression or cell number in adult mice. Interestingly, we identified two interspersed subpopulations of Rfrp cells (high Rfrp-expressing, HE; low Rfrp-expressing, LE), which have unique developmental and steroidal regulation characteristics. The number of LE cells robustly decreases during postnatal development, whereas HE cell number increases significantly before puberty. Using Bax knockout mice, we determined that the dramatic developmental decrease in LE Rfrp cells is not due primarily to BAX-dependent apoptosis. In adults, we found that estradiol and testosterone moderately repress Rfrp expression in both HE and LE cells, whereas the nonaromatizable androgen dihydrotestosterone has no effect. Using double-label in situ hybridization, we determined that approximately 25% of Rfrp neurons coexpress estrogen receptor-α in each sex, whereas Rfrp cells do not readily express androgen receptor in either sex, regardless of hormonal milieu. Lastly, when we looked at RFRP-3 receptors, we detected some coexpression of Gpr147 but no coexpression of Gpr74 in GnRH neurons of both intact and gonadectomized males and females. Thus, RFRP-3 may exert its effects on reproduction either directly, via Gpr147 in a subset of GnRH neurons, and/or indirectly, via upstream regulators of GnRH.
116 citations
Cites methods from "Temporal phase relation of circadia..."
...Similar data obtained by quantifying RFRP-3-ir in male mice showed a decrease in RFRP-3-ir cell number after sexual maturation (20, 21), but developmental changes in Rfrp mRNA were not measured in mice, and females were not studied....
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TL;DR: Gonadotropin-inhibitory hormone (GnIH) is a hypothalamic neuropeptide that was isolated from the brains of Japanese quail in 2000, which inhibited luteinizing hormone release from the anterior pituitary gland.
81 citations
Cites background from "Temporal phase relation of circadia..."
...One form is GnRH1 which is released at the median eminence to stimulate gonadotropin secretion from the anterior pituitary gland (King and Millar, 1982; Miyamoto et al., 1982; Sharp et al., 1990; Ubuka and Bentley, 2009, 2010; Ubuka et al., 2009a)....
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TL;DR: It is hypothesized that interaction between GnRH I-RFRP-3 neuropeptides may be involved in the regulation of follicular development and atresia.
Abstract: Gonadotropin releasing hormone (GnRH) has now been suggested as an important intraovarian regulatory factor. Gonadotropin inhibitory hormone (GnIH) a hypothalamic dodecapeptide, acts opposite to GnRH. GnRH, GnIH and their receptors have been demonstrated in the gonads. In order to find out the physiological significance of these neuropeptides in the ovary, we aim to investigate changes in the abundance of GnRH I and GnIH in the ovary of mice during estrous cycle. The present study investigated the changes in GnRH I, GnRH I-receptor and RFRP-3 protein expression in the ovary of mice during estrous cycle by immunohistochemistry and immunoblot analysis. The immunoreactivity of GnRH I and its receptor and RFRP-3 were mainly localized in the granulosa cells of the healthy and antral follicles during proestrus and estrus and in the luteal cells during diestrus 1 and 2 phases. The relative abundance of immunoreactivity of GnRH I, GnRH I-receptor and RFRP-3 undergo significant variation during proestrus and thus may be responsible for selection of follicle for growth and atresia. A significant increase in the concentration of RFRP-3 during late diestrus 2 coincided with the decline in corpus luteum activity and initiation of follicular growth and selection. In general, immunolocalization of GnRH I, GnRH I-receptor and RFRP-3 were found in close vicinity suggesting functional interaction between these peptides. It is thus, hypothesized that interaction between GnRH I-RFRP-3 neuropeptides may be involved in the regulation of follicular development and atresia.
68 citations
Cites background or methods from "Temporal phase relation of circadia..."
...The specificity of the GnIH antibody has been checked by a competitive ELISA (Ukena and Tsutsui 2001; Ukena et al. 2002; Kriegsfeld et al. 2006; Gibson et al. 2008; Ubuka et al. 2009; Sethi et al. 2010a, b; Zhao et al. 2010)....
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...RFRP-3-ir has been investigated in the brain of several rodent species, photoperiodic Syrian hamsters (Mesocricetus auratus), and less photoperiodic rats (Rattus novegicus) and mice (Mus musculus) (Kriegsfeld et al. 2006; Ukena and Tsutsui 2001; Sethi et al. 2010a)....
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...RFRP-3-ir has been investigated in the brain of several rodent species like Syrian hamster, rat and mice (Kriegsfeld et al. 2006; Sethi et al. 2010a, b; Ukena and Tsutsui 2001) and mammalian testes during spermatogenic cycle (Zhao et al. 2010)....
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TL;DR: Gonadotropin-inhibitory hormone has therapeutic potential in the treatment of reproductive cycle and hormone-dependent diseases, such as precocious puberty, endometriosis, uterine fibroids, and prostatic and breast cancers.
Abstract: Gonadotropin-inhibitory hormone (GnIH) was first identified in the Japanese quail as a hypothalamic neuropeptide inhibitor of gonadotropin secretion. Subsequent studies have shown that GnIH is present in the brains of birds including songbirds, and mammals including humans. The identified avian and mammalian GnIH peptides universally possess an LPXRFamide (X = L or Q) motif at their C-termini. Mammalian GnIH peptides are also designated as RFamide-related peptides from their structures. The receptor for GnIH is the G protein-coupled receptor 147 (GPR147), which is thought to be coupled to Gαi protein. Cell bodies of GnIH neurons are located in the paraventricular nucleus (PVN) in birds and the dorsomedial hypothalamic area (DMH) in mammals. GnIH neurons in the PVN or DMH project to the median eminence to control anterior pituitary function. GPR147 is expressed in the gonadotropes and GnIH suppresses synthesis and release of gonadotropins. It was further shown in immortalized mouse gonadotrope cell line (LT2 cells) that GnIH inhibits gonadotropin-releasing hormone (GnRH) induced gonadotropin subunit gene transcriptions by inhibiting adenylate cyclase/cAMP/PKA dependent ERK pathway. GnIH neurons also project to GnRH neurons in the preoptic area, and GnRH neurons express GPR147 in birds and mammals. Accordingly, GnIH may inhibit gonadotropin synthesis and release by decreasing the activity of GnRH neurons as well as directly acting on the gonadotropes. GnIH also inhibits reproductive behavior possibly by acting within the brain. GnIH expression is regulated by a nocturnal hormone melatonin and stress in birds and mammals. Accordingly, GnIH may play a role in translating environmental information to inhibit reproductive physiology and behavior of birds and mammals. Finally, GnIH has therapeutic potential in the treatment of reproductive cycle and hormone-dependent diseases, such as precocious puberty, endometriosis, uterine fibroids, and prostatic and breast cancers.
50 citations
Cites background from "Temporal phase relation of circadia..."
...There are also reports showing the correlation of RFRP expression and testicular activities of male mice (Sethi et al., 2010a,b)....
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TL;DR: This work represents the first study reporting the effects of rearing temperature on the transcription of gnih system genes, as well as its daily variations during the development of a fish species.
Abstract: The role of rearing temperature on fish development, sex differentiation and puberty has been largely addressed, but the impact of water temperature on the ontogeny of the main neuroendocrine systems controlling reproduction has received little attention. Gonadotropin-inhibitory hormone (GnIH) has been shown to act on gonadotropin-releasing hormone (GnRH) neurons and on the pituitary to inhibit gonadotropin release and synthesis in vertebrates, including sea bass, Dicentrarchus labrax. In the present study we investigated the effects of rearing temperature during the thermosensitive period (5–60 days post-fertilization, dpf) on the expression of the GnIH gene (gnih) and its receptor (gnihr). Animals were maintained under two different conditions, low temperature (LT, 15 °C) or high temperature (HT, 21 °C), throughout the thermosensitive period and sampled from 5 to 360 dpf at mid-light (ML) and mid-dark (MD). Our results showed significant effects of temperature on gnih and gnihr expression during the thermosensitive period, with higher transcript levels under LT condition. Some differences were also evident after the completion of the sex differentiation process. Moreover, we revealed daily variations in the developmental expression of gnih and gnihr, with higher diurnal mRNA levels at early stages (until 25 dpf), and a shift to higher nocturnal expression levels at 300–360 dpf, which corresponded with the beginning of the winter (reproductive season). To the best of our knowledge, this work represents the first study reporting the effects of rearing temperature on the transcription of gnih system genes, as well as its daily variations during the development of a fish species.
28 citations
References
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TL;DR: It is shown, in a bird, that the hypothalamus also contains a novel peptide which inhibits gonadotropin release, the first hypothalamic peptide inhibiting gonadotropic hormone reported in a vertebrate.
760 citations
TL;DR: In this paper, the identification of a human gene that encodes at least three RFamide-related peptides, hRFRP-1-3, has been reported.
Abstract: Only a few RFamide peptides have been identified in mammals, although they have been abundantly found in invertebrates. Here we report the identification of a human gene that encodes at least three RFamide-related peptides, hRFRP-1-3. Cells transfected with a seven-transmembrane-domain receptor, OT7T022, specifically respond to synthetic hRFRP-1 and hRFRP-3 but not to hRFRP-2. RFRP and OT7T022 mRNAs are expressed in particular regions of the rat hypothalamus, and intracerebroventricular administration of hRFRP-1 increases prolactin secretion in rats. Our results indicate that a variety of RFamide-related peptides may exist and function in mammals.
556 citations
TL;DR: The distribution of GnIH efferents to neural sites regulating reproductive behavior and neuroendocrine secretions, expression of steroid receptors in GnIh-ir nuclei, and GnI H inhibition of luteinizing hormone secretion indicate the discovery of a system regulating the mammalian reproductive axis.
Abstract: Successful reproduction requires maintenance of the reproductive axis within fine operating limits through negative feedback actions of sex steroids. Despite the importance of this homeostatic process, our understanding of the neural loci, pathways, and neurochemicals responsible remain incomplete. Here, we reveal a neuropeptidergic pathway that directly links gonadal steroid actions to regulation of the reproductive system. An RFamide (Arg-Phe-NH2) peptide that inhibits gonadotropin release from quail pituitary was recently identified and named gonadotropin-inhibitory hormone (GnIH). Birds are known to have specialized adaptations associated with gonadotropin-releasing hormone (GnRH) regulation to optimize reproduction (e.g., encephalic photoreceptors), and the existence of a hypothalamic peptide inhibiting gonadotropins may or may not be another such specialization. To determine whether GnIH serves as a signaling pathway for sex steroid regulation of the reproductive axis, we used immunohistochemistry and in situ hybridization to characterize the distribution and functional role of this peptide in hamsters, rats, and mice. GnIH-immunoreactive (GnIH-ir) cell bodies are clustered in the mediobasal hypothalamus with pronounced projections and terminals throughout the CNS. In vivo GnIH administration rapidly inhibits luteinizing hormone secretion. Additionally, GnIH-ir neurons form close appositions with GnRH cells, suggesting a direct means of GnRH modulation. Finally, GnIH-ir cells express estrogen receptor-α and exhibit robust immediate early gene expression after gonadal hormone stimulation. Taken together, the distribution of GnIH efferents to neural sites regulating reproductive behavior and neuroendocrine secretions, expression of steroid receptors in GnIH-ir nuclei, and GnIH inhibition of luteinizing hormone secretion indicate the discovery of a system regulating the mammalian reproductive axis.
529 citations
TL;DR: Results indicate that although RFRP-3 has similar effects on LH as observed with GnIH in avian species, in the rat RFRPs has additional roles in regulating feeding and growth.
378 citations