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

Matthew C Poling,Alexander S Kauffman

doi:10.3389/fendo.2015.00150

Matthew C Poling, Alexander S Kauffman

Open Access

https://doi.org/10.3389/fendo.2015.00150

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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.

Highlights

Since their identification 15 years ago, both gonadotropin-inhibiting hormone (GnIH) and its mammalian ortholog, RFamide-related peptide (RFRP-3), have become important research focuses of neuroendocrinologists and reproductive biologists
The primary focus of this review, RFamide-related peptide-3 (RFRP-3) is thought to regulate luteinizing hormone (LH) secretion through inhibition of gonadotropin-releasing hormone (GnRH) neurons rather than by direct action on the pituitary. This model is supported by data, collected primarily in adult animals, showing that RFRP-3 neural fibers appose GnRH neurons [2, 9, 10], RFRP-3’s high affinity receptor, Gpr147, is expressed in some GnRH neurons [11], GnRH neuron electrical firing changes when RFRP-3 is applied to hypothalamic explants [4, 5], and RFRP-3 treatment suppresses LH secretion in a Regulation and development of RFRP-3 neurons
In regards to RFRP-3, we found that a small subset of Rfrp neurons express the long form leptin receptor mRNA, suggesting that leptin could potentially act directly in those neurons

Summary

Introduction

Since their identification 15 years ago, both gonadotropin-inhibiting hormone (GnIH) and its mammalian ortholog, RFamide-related peptide (RFRP-3), have become important research focuses of neuroendocrinologists and reproductive biologists. We found that the total number of detectable Rfrp cells was highest at birth and significantly dropped through all postnatal ages, with the fewest Rfrp neurons present in adulthood This developmental pattern of Rfrp neurons was the same for both sexes [20]. The total number of Rfrp cells was found to decrease around PND20-21, around weaning and ~1 week before the onset of female puberty [21] This outcome differs from the previously published qRTPCR rat experiments [18, 19], as neither of those studies showed a consistent decrease in Rfrp expression between prepubertal and adult animals. This conclusion is supported by both mRNA and protein data in several species, but the functional significance of this developmental change remains to be determined

What Regulates Developmental Changes in Neural Rfrp Expression?

Conclusion