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Regulation and Function of RFRP-3 (GnIH) Neurons during Postnatal Development.

Poling MC, Kauffman AS - Front Endocrinol (Lausanne) (2015)

Bottom Line: Here, we discuss the latest evidence relating to RFRP-3 neuron regulation and function during development and sexual maturation, focusing on rodents.We highlight significant changes in RFRP-3 and Rfrp expression, as well as RFRP-3 neuronal activation, during key stages of postnatal and pubertal development and also discuss recent evidence testing the requisite role of RFRP-3 receptors for normal pubertal timing and developmental LH secretion.Interestingly, some findings suggest that endogenous RFRP-3 signaling may not be necessary for the puberty timing, at least in some species, forcing new hypotheses to be generated regarding this peptide's functional significance to sexual maturation and development.

View Article: PubMed Central - PubMed

Affiliation: Department of Reproductive Medicine, University of California, San Diego , La Jolla, CA , USA.

ABSTRACT
RFamide-related peptide-3 (RFRP-3) [mammalian ortholog to gonadotropin-inhibiting hormone (GnIH)] potently inhibits gonadotropin secretion in mammals. Studies of RFRP-3 immunoreactivity and Rfrp expression (the gene encoding RFRP-3) in mammalian brains have uncovered several possible pathways regulating RFRP-3 neurons, shedding light on their potential role in reproduction and other processes, and pharmacological studies have probed the target sites of RFRP-3 action. Despite this, there is currently no major consensus on RFRP-3's specific endogenous role(s) in reproductive physiology. Here, we discuss the latest evidence relating to RFRP-3 neuron regulation and function during development and sexual maturation, focusing on rodents. We highlight significant changes in RFRP-3 and Rfrp expression, as well as RFRP-3 neuronal activation, during key stages of postnatal and pubertal development and also discuss recent evidence testing the requisite role of RFRP-3 receptors for normal pubertal timing and developmental LH secretion. Interestingly, some findings suggest that endogenous RFRP-3 signaling may not be necessary for the puberty timing, at least in some species, forcing new hypotheses to be generated regarding this peptide's functional significance to sexual maturation and development.

No MeSH data available.


Related in: MedlinePlus

Schematic depicting how Rfrp neurons may fit into mouse neuroanatomy and physiology. Sex steroids are known to inhibit Rfrp expression, primarily through estrogen pathways, while leptin appears to have no major direct effect on Rfrp neurons, at least in development. There appear to be other developmental factors that regulate the development of Rfrp expression which are both stimulatory and inhibitory that remain to be determined. RFRP-3 neurons have efferents that may regulate LH secretion by acting directly on GnRH neurons, or indirectly on GnRH neurons through arcuate kisspeptin neurons or other yet-to-be identified neuronal populations. Other RFRP-3 neuronal target areas include the paraventricular nucleus (PVN) and the spinal cord, and RFRP-3 has unknown effects on these non-reproductive regions.
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Figure 2: Schematic depicting how Rfrp neurons may fit into mouse neuroanatomy and physiology. Sex steroids are known to inhibit Rfrp expression, primarily through estrogen pathways, while leptin appears to have no major direct effect on Rfrp neurons, at least in development. There appear to be other developmental factors that regulate the development of Rfrp expression which are both stimulatory and inhibitory that remain to be determined. RFRP-3 neurons have efferents that may regulate LH secretion by acting directly on GnRH neurons, or indirectly on GnRH neurons through arcuate kisspeptin neurons or other yet-to-be identified neuronal populations. Other RFRP-3 neuronal target areas include the paraventricular nucleus (PVN) and the spinal cord, and RFRP-3 has unknown effects on these non-reproductive regions.

Mentions: RFamide-related peptide-3 suppresses LH secretion when given exogenously. However, additional exploration into RFRP-3’s functional position in the mammalian reproductive axis has been limited. RFRP-3 neurons have distinct and quantifiable changes throughout development, hinting at a role in regulating puberty, but this was not corroborated by knockout and knockdown studies. Thus, RFRP-3’s developmental function is not immediately clear (Figure 2). Knockout mouse studies have shown that RFRP-3 neuron development is not strongly regulated by BAX-mediated apoptosis or by leptin, opening the possibility of other novel mechanisms that may influence the maturation of RFRP-3 neurons (Figure 2). Thus, RFRP-3’s specific developmental role is still being elucidated, leaving multiple avenues to explore. How does RFRP-3 regulate LH secretion in prepubertal animals, and why is it influenced by estrogen? Why does RFRP-3 neuron activation decrease after weaning? Why do some Rfrp neurons express high levels of Rfrp mRNA while others do not? Is there a functional significance to the robust Rfrp changes between birth and juvenile life and then again before adulthood? Answering these questions will further identify the role of RFRP-3 in development and reproduction in general.


Regulation and Function of RFRP-3 (GnIH) Neurons during Postnatal Development.

Poling MC, Kauffman AS - Front Endocrinol (Lausanne) (2015)

Schematic depicting how Rfrp neurons may fit into mouse neuroanatomy and physiology. Sex steroids are known to inhibit Rfrp expression, primarily through estrogen pathways, while leptin appears to have no major direct effect on Rfrp neurons, at least in development. There appear to be other developmental factors that regulate the development of Rfrp expression which are both stimulatory and inhibitory that remain to be determined. RFRP-3 neurons have efferents that may regulate LH secretion by acting directly on GnRH neurons, or indirectly on GnRH neurons through arcuate kisspeptin neurons or other yet-to-be identified neuronal populations. Other RFRP-3 neuronal target areas include the paraventricular nucleus (PVN) and the spinal cord, and RFRP-3 has unknown effects on these non-reproductive regions.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4585233&req=5

Figure 2: Schematic depicting how Rfrp neurons may fit into mouse neuroanatomy and physiology. Sex steroids are known to inhibit Rfrp expression, primarily through estrogen pathways, while leptin appears to have no major direct effect on Rfrp neurons, at least in development. There appear to be other developmental factors that regulate the development of Rfrp expression which are both stimulatory and inhibitory that remain to be determined. RFRP-3 neurons have efferents that may regulate LH secretion by acting directly on GnRH neurons, or indirectly on GnRH neurons through arcuate kisspeptin neurons or other yet-to-be identified neuronal populations. Other RFRP-3 neuronal target areas include the paraventricular nucleus (PVN) and the spinal cord, and RFRP-3 has unknown effects on these non-reproductive regions.
Mentions: RFamide-related peptide-3 suppresses LH secretion when given exogenously. However, additional exploration into RFRP-3’s functional position in the mammalian reproductive axis has been limited. RFRP-3 neurons have distinct and quantifiable changes throughout development, hinting at a role in regulating puberty, but this was not corroborated by knockout and knockdown studies. Thus, RFRP-3’s developmental function is not immediately clear (Figure 2). Knockout mouse studies have shown that RFRP-3 neuron development is not strongly regulated by BAX-mediated apoptosis or by leptin, opening the possibility of other novel mechanisms that may influence the maturation of RFRP-3 neurons (Figure 2). Thus, RFRP-3’s specific developmental role is still being elucidated, leaving multiple avenues to explore. How does RFRP-3 regulate LH secretion in prepubertal animals, and why is it influenced by estrogen? Why does RFRP-3 neuron activation decrease after weaning? Why do some Rfrp neurons express high levels of Rfrp mRNA while others do not? Is there a functional significance to the robust Rfrp changes between birth and juvenile life and then again before adulthood? Answering these questions will further identify the role of RFRP-3 in development and reproduction in general.

Bottom Line: Here, we discuss the latest evidence relating to RFRP-3 neuron regulation and function during development and sexual maturation, focusing on rodents.We highlight significant changes in RFRP-3 and Rfrp expression, as well as RFRP-3 neuronal activation, during key stages of postnatal and pubertal development and also discuss recent evidence testing the requisite role of RFRP-3 receptors for normal pubertal timing and developmental LH secretion.Interestingly, some findings suggest that endogenous RFRP-3 signaling may not be necessary for the puberty timing, at least in some species, forcing new hypotheses to be generated regarding this peptide's functional significance to sexual maturation and development.

View Article: PubMed Central - PubMed

Affiliation: Department of Reproductive Medicine, University of California, San Diego , La Jolla, CA , USA.

ABSTRACT
RFamide-related peptide-3 (RFRP-3) [mammalian ortholog to gonadotropin-inhibiting hormone (GnIH)] potently inhibits gonadotropin secretion in mammals. Studies of RFRP-3 immunoreactivity and Rfrp expression (the gene encoding RFRP-3) in mammalian brains have uncovered several possible pathways regulating RFRP-3 neurons, shedding light on their potential role in reproduction and other processes, and pharmacological studies have probed the target sites of RFRP-3 action. Despite this, there is currently no major consensus on RFRP-3's specific endogenous role(s) in reproductive physiology. Here, we discuss the latest evidence relating to RFRP-3 neuron regulation and function during development and sexual maturation, focusing on rodents. We highlight significant changes in RFRP-3 and Rfrp expression, as well as RFRP-3 neuronal activation, during key stages of postnatal and pubertal development and also discuss recent evidence testing the requisite role of RFRP-3 receptors for normal pubertal timing and developmental LH secretion. Interestingly, some findings suggest that endogenous RFRP-3 signaling may not be necessary for the puberty timing, at least in some species, forcing new hypotheses to be generated regarding this peptide's functional significance to sexual maturation and development.

No MeSH data available.


Related in: MedlinePlus