Evolutionary Origin of the Structure and Function of Gonadotropin-Inhibitory Hormone: Insights from Lampreys

Abstract

Gonadotropin (GTH)-inhibitory hormone (GnIH) is a novel hypothalamic neuropeptide that inhibits GTH secretion in mammals and birds by acting on gonadotropes and GnRH neurons within the hypothalamic-pituitary-gonadal axis. GnIH and its orthologs that have an LPXRFamide (X = L or Q) motif at the C terminus (LPXRFamide peptides) have been identified in representative species of gnathostomes. However, the identity of an LPXRFamide peptide had yet to be identified in agnathans, the most ancient lineage of vertebrates, leaving open the question of the evolutionary origin of GnIH and its ancestral function(s). In this study, we identified an LPXRFamide peptide gene encoding three peptides (LPXRFa-1a, LPXRFa-1b, and LPXRFa-2) from the brain of sea lamprey by synteny analysis and cDNA cloning, and the mature peptides by immunoaffinity purification and mass spectrometry. The expression of lamprey LPXRFamide peptide precursor mRNA was localized in the brain and gonad by RT-PCR and in the hypothalamus by in situ hybridization. Immunohistochemistry showed appositions of lamprey LPXRFamide peptide immunoreactive fibers in close proximity to GnRH-III neurons, suggesting that lamprey LPXRFamide peptides act on GnRH-III neurons. In addition, lamprey LPXRFa-2 stimulated the expression of lamprey GnRH-III protein in the hypothalamus and GTHβ mRNA expression in the pituitary. Synteny and phylogenetic analyses suggest that the LPXRFamide peptide gene diverged from a common ancestral gene likely through gene duplication in the basal vertebrates. These results suggest that one ancestral function of LPXRFamide peptides may be stimulatory compared with the inhibitory function seen in later-evolved vertebrates (birds and mammals).

The Evolution and Variety of RFamide-Type Neuropeptides: Insights from Deuterostomian Invertebrates

“…Analysis of the phylogenetic distribution of GnIH-type neuropeptides has revealed that they occur throughout the vertebrates, from primitive agnathan vertebrates through bony fish and amphibians to reptiles, birds, and mammals (25, 26). A comprehensive survey of the properties and functions of GnIH-type neuropeptides in each of the vertebrate classes is beyond the scope of this review and has been discussed elsewhere.…”

“…Therefore, we will focus here on studies in the most primitive extant vertebrates, the agnathans (lamprey, hagfish). A cDNA encoding a precursor of two GnIH-type peptides has been identified in the sea lamprey Petromyzon marinus , with expression revealed in the hypothalamus and gonads (26). Interestingly, injection of the GnIH-type peptides stimulates expression of GnRH and gonadotropins in lamprey, which contrasts with the inhibitory effects of GnIH in birds and mammals.…”

“…Interestingly, injection of the GnIH-type peptides stimulates expression of GnRH and gonadotropins in lamprey, which contrasts with the inhibitory effects of GnIH in birds and mammals. Thus, the physiological role of GnIH as a regulator of reproductive processes can be traced back to the common ancestor of vertebrates, but inhibitory or stimulatory effects are observed in different vertebrate lineages (26). …”

“…The lamprey sequences are from Ref. (26), other vertebrate and B. floridae sequences are from Ref. (8), the Lottia gigantea sequences are from Ref.…”

Evolutionary Origin of GnIH and NPFF in Chordates: Insights from Novel Amphioxus RFamide Peptides

“…The structure of their receptors also showed high sequence similarity. In addition, synteny analyses showed that GnIH gene and NPFF gene are both located near the HOX clusters [23], [24]. Because the HOX clusters are considered to have duplicated from a common ancestral gene during whole-genome duplication events through vertebrate evolution [25], GnIH gene and NPFF gene may also have diverged through whole-genome duplication in the course of evolution in vertebrates [23], [24].…”