Evolutionary origin and divergence of GnIH and its homologous peptides

doi:10.1016/j.ygcen.2008.10.002

General and Comparative Endocrinology

Volume 161, Issue 1, March 2009, Pages 30-33

https://doi.org/10.1016/j.ygcen.2008.10.002 Get rights and content

Abstract

Probing undiscovered hypothalamic neuropeptides that play important roles in the regulation of pituitary function in vertebrates is essential for the progress of neuroendocrinology. In 2000, we discovered a novel hypothalamic dodecapeptide inhibiting gonadotropin release in quail and termed it gonadotropin-inhibitory hormone (GnIH). GnIH acts on the pituitary and gonadotropin-releasing hormone (GnRH) neurons in the hypothalamus via a novel G protein-coupled receptor for GnIH to inhibit gonadal development and maintenance by decreasing gonadotropin release and synthesis. Similar findings were observed in other avian species. Thus, GnIH is a key factor controlling avian reproduction. To give our findings a broader perspective, we also found GnIH homologous peptides in the hypothalamus of other vertebrates, such as mammals, reptiles, amphibians and teleosts. GnIH and its homologs share a common C-terminal LPXRFamide (X = L or Q) motif. A mammalian GnIH homolog also inhibited gonadotropin release in mammals like the GnIH action in birds. In contrast to higher vertebrates, hypophysiotropic activities of GnIH homologs were different in lower vertebrates. To clarify the evolutionary origin of GnIH and its homologs, we further sought to identify novel LPXRFamide peptides from the brain of sea lamprey and hagfish, two extant groups of the oldest lineage of vertebrates, Agnatha. In these agnathans, LPXRFamide peptide and its cDNA were identified only from the brain of hagfish. Based on these findings over the past decade, this paper summarizes the evolutionary origin and divergence of GnIH and its homologous peptides.

Introduction

In vertebrates, the neuropeptide control of gonadotropin secretion is primarily through the stimulatory action of the hypothalamic decapeptide, gonadotropin-releasing hormone (GnRH). GnRH regulates secretion of both of the gonadotropins luteinizing hormone (LH) and follicle-stimulating hormone (FSH) and acts as a key neurohormone for vertebrate reproduction. Since the discovery of GnRH in the brain of mammals (Matsuo et al., 1971, Burgus et al., 1972), several other GnRHs have been identified in the brain of nonmammals (King and Millar, 1982, Miyamoto et al., 1982, Miyamoto et al., 1984, Sherwood et al., 1983, Sherwood et al., 1986). Until recently, no neuropeptide acting at the level of the pituitary to regulate gonadotropin secretion negatively has been discovered in vertebrates, although gonadal sex steroids and inhibin inhibit gonadotropin secretion via feedback from the gonads.

In 2000, we identified a novel hypothalamic dodecapeptide which directly acts on the pituitary to inhibit gonadotropin release in quail and termed it gonadotropin-inhibitory hormone (GnIH; Tsutsui et al., 2000). The discovery of GnIH has opened the door to an entirely new line of research within the realm of reproductive neuroendocrinology. From the past 8 years of research, we now know that GnIH exists in several avian species and acts as a newly discovered neurohormone for the regulation of avian reproduction by decreasing gonadotropin release and synthesis.

Because a gonadotropin-inhibitory system by GnIH is a new finding, we have also identified GnIH homologous peptides in the hypothalamus of other vertebrates, such as mammals, reptiles, amphibians and teleosts. GnIH and its homologs share a common C-terminal LPXRFamide (X = L or Q) motif (i.e., LPXRFamide peptides). The orthologous relationship of LPXRFamide peptide genes was confirmed by the identification of conserved synteny at the chromosome level among three classes of vertebrates, such as mammal (human), bird (chicken), and bony fish (torafugu) (Ikemoto and Park, 2005). Interestingly, GnIH and its homologs act on the regulation of pituitary function, but hypophysiotropic activities of these LPXRFamide peptides are different in vertebrates, particularly in lower vertebrates. To clarify the evolutionary origin of GnIH and its homologs, we further sought to identify novel LPXRFamide peptides from the brain of sea lamprey and hagfish, two extant groups of the oldest lineage of vertebrates, Agnatha. LPXRFamide peptide and its cDNA were identified only from the brain of hagfish. Hagfish LPXRFamide peptide may be the most ancestral feature of LPXRFamide peptides.

Section snippets

Discovery of GnIH and its mode of action and functional significance

The molluscan cardioexcitatory neuropeptide Phe-Met-Arg-Phe-NH₂ (FMRFamide) was first found in the ganglia of the venus clam, Macrocallista nimbosa (Price and Greenberg, 1977), and subsequently, immunohistochemical studies using an antiserum against FMRFamide suggested that the vertebrate nervous systems also contain some unknown neuropeptides that possess the RFamide motif at their C-termini (i.e., RFamide peptides) (Raffa, 1988, Rastogi et al., 2001). We therefore looked for a novel RFamide

Divergence of GnIH and its homologous peptides

To give our findings a broader perspective, we further sought to identify neuropeptides closely related to GnIH, namely GnIH homologous peptides, in other vertebrates. GnIH homologous peptides were identified in the hypothalamus of a variety of vertebrates, such as mammals (RFRPs; Fukusumi et al., 2001, Ukena et al., 2002, Yoshida et al., 2003), reptiles (unpublished observation), amphibians (fGRP and fGRP-RPs; Koda et al., 2002, Sawada et al., 2002a, Ukena et al., 2003a), R-RFa; Chartrel et

Evolutionary origin of GnIH and its homologous peptides

To clarify the evolutionary origin of GnIH and its homologs, we further investigated novel LPXRFamide peptides from the brain of sea lamprey and, two extant groups of the oldest lineage of vertebrates, Agnatha. In the brain of sea lamprey, we identified three PQRFamide peptides, another RFamide peptide group in the RFamide peptide family (Osugi et al., 2006). Lamprey PQRFamide peptides have the C-terminal structure PQRFamide similar to LPXRFamide peptides (X = L or Q). We also identified a cDNA

Summary

GnIH, a newly discovered avian hypothalamic neuropeptide, is an important factor in the control of avian reproduction. The discovery of GnIH has opened avenues for a new research field in reproductive neuroendocrinology. To give our findings a broader perspective, we also found GnIH homologous peptides in the hypothalamus of other vertebrates, such as mammals, reptiles, amphibians and teleosts. GnIH and its homologs share a common C-terminal LPXRFamide (X = L or Q) motif. A mammalian GnIH homolog

Acknowledgments

This work was supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Science and Culture, Japan (15207007, 16086206 and 18107002 to K.T.).

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GnIH is associated with behaviors important for survival and reproduction, such as the stress response (Calisi et al., 2008; Kirby et al., 2009), feeding behaviors (Tachibana et al., 2005; Johnson et al., 2007; Klingerman et al., 2011; Clarke et al., 2012), and social, environmental, and reproductive behaviors (Bentley et al., 2006a; Small et al., 2008; Calisi et al., 2011; Ubuka et al., 2013; Piekarski et al., 2013; Ubuka et al., 2014). We also have information regarding changes in the structure and function of this neuropeptide in various taxa (Greives et al., 2008; Tsutsui and Osugi, 2009; Tsutsui et al., 2010c). The use of an integrative framework like Tinbergen’s can reveal patterns not evident from studies that focus on just one question (Fig 2).
The integration of various fields of investigation is of key importance to fully comprehending endocrine function. Here, I enact the theoretical framework of Nikolaas Tinbergen’s four questions for understanding behavior to help bridge the wide gap that exists between our relatively reductionist molecular knowledge of a particular neurohormone, gonadotropin-inhibitory hormone (GnIH), and its place in animal behavior. Hypothalamic GnIH, upon its discovery in 2000, was so named because of its inhibitory effect on the release of the gonadotropins, luteinizing hormone (LH) and follicle stimulating hormone (FSH), from the pituitary. Because gonadotropins are necessary for reproduction, this finding stimulated questions about the functional significance of GnIH in reproduction and sexual behavior. After over a decade of research, invaluable knowledge has been gained regarding the mechanistic attributes of GnIH (mammalian homolog, RFamide-related peptide (RFRP)) in a variety of vertebrate species. However, many questions remain regarding the effect of the environment on GnIH and the subsequent effects of GnIH on behavior. I review the role of GnIH in shaping behavior using the framework of Tinbergen’s four questions of mechanism, ontogeny, function and phylogeny. The studies I review were conducted in various species of mammals, birds, and in one species of fish. Because GnIH can play a role in mediating behaviors such as those important for reproduction, sociality, feeding, and the stress response in a variety of species, an integrative approach to the study of GnIH will help provide a multipronged schema for answering questions of GnIH function. By using the framework highlighted by Tinbergen’s four questions, we will deepen and enhance our knowledge of the role of hormones in behavior from the point of view of the mechanisms involved.

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MinireviewEvolutionary origin and divergence of GnIH and its homologous peptides

Abstract

Introduction

Section snippets

Discovery of GnIH and its mode of action and functional significance

Divergence of GnIH and its homologous peptides

Evolutionary origin of GnIH and its homologous peptides

Summary

Acknowledgments

Peptides

Biochim. Biophys. Acta.

Horm. Behav.

J. Biol. Chem.

Biochem. Biophys. Res. Commun.

Biochem. Biophys. Res. Commun.

Peptides

J. Biol. Chem.

Gen. Comp. Endocrinol.

Biochem. Biophys. Res. Commun.

Peptides

A novel rat hypothalamic RFamide-related peptide identified by immunoaffinity chromatography and mass spectrometry FEBS Lett.

Biochim. Biophys. Acta

Novel fish hypothalamic neuropeptides stimulate the release of gonadotrophins and growth hormone from the pituitary of sockeye salmon

J. Endocrinol.

Gonadotropin-inhibitory peptide in song sparrows (Melospiza melodia) in different reproductive conditions, and in house sparrows (Passer domesticus) relative to chicken gonadotropin-releasing hormone

J. Neuroendocrinol.

Primary structure of the ovine hypothalamic luteinizing hormone-releasing factor (LRF)

Proc. Natl. Acad. Sci. USA

Isolation, characterization, and distribution of a novel neuropeptide, Rana RFamide (R-RFa), in the brain of the European green frog Rana esculenta

J. Comp. Neurol.

Gonadotrophin inhibitory hormone depresses gonadotrophin α and follicle-stimulating hormone β subunit expression in the pituitary of the domestic chicken

J. Neuroendocrinol.

A novel active pentapeptide from chicken brain identified by antibodies to FMRFamide

Nature

New neuropeptides containing carboxy-terminal RFamide and their receptor in mammals

Nat. Cell Biol.

Minireview
Evolutionary origin and divergence of GnIH and its homologous peptides