In 2000, we discovered a novel hypothalamic neuropeptide that actively inhibits gonadotrophin release in quail and termed it gonadotrophin-inhibitory hormone (GnIH). GnIH peptides have subsequently been identified in most representative species of gnathostomes. They all share a C-terminal LPXRFamide (X = L or Q) motif. GnIH can inhibit gonadotrophin synthesis and release by decreasing the activity of GnRH neuroes, as well as by directly inhibiting pituitary gonadotrophin secretion in birds and mammals. To investigate the evolutionary origin of GnIH and its ancestral function, we identified a GnIH precursor gene encoding GnIHs from the brain of sea lamprey, the most ancient lineage of vertebrates. Lamprey GnIHs possess a C-terminal PQRFamide motif. In vivo administration of one of lamprey GnIHs stimulated the expression of lamprey GnRH in the hypothalamus and gonadotophin β mRNA in the pituitary. Thus, GnIH may have emerged in agnathans as a stimulatory neuropeptide that subsequently diverged to an inhibitory neuropeptide during the course of evolution from basal vertebrates to later-evolved vertebrates, such as birds and mammals. From a structural point of view, pain modulatory neuropeptides, such as neuropeptide FF (NPFF) and neuropeptide AF, share a C-terminal PQRFamide motif. Because agnathans possess both GnIH and NPFF genes, the origin of GnIH and NPFF genes may date back before the emergence of agnathans. More recently, we identified a novel gene encoding RFamide peptides in the amphioxus. Molecular phylogenetic analysis and synteny analysis indicated that this gene is closely related to the genes of GnIH and NPFF of vertebrates. The results suggest that the identified protochordate gene is similar to the common ancestor of GnIH and NPFF genes, indicating that the origin of GnIH and NPFF may date back to the time of the emergence of early chordates. The GnIH and NPFF genes may have diverged by whole-genome duplication during the course of vertebrate evolution.
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