Abstract
Discovery of gonadotropin-inhibitory hormone (GnIH) in the Japanese quail in 2000 was the first to demonstrate the existence of a hypothalamic neuropeptide inhibiting gonadotropin release. We now know that GnIH regulates reproduction by inhibiting gonadotropin synthesis and release via action on the gonadotropin-releasing hormone (GnRH) system and the gonadotrope in various vertebrates. GnIH peptides identified in birds and mammals have a common LPXRF-amide (X = L or Q) motif at the C-terminus and inhibit pituitary gonadotropin secretion. However, the function and structure of GnIH peptides are diverse in fish. Goldfish GnIHs possessing a C-terminal LPXRF-amide motif have both stimulatory and inhibitory effects on gonadotropin synthesis or release. The C-terminal sequence of grass puffer and medaka GnIHs are MPQRF-amide. To investigate the evolutionary origin of GnIH and its ancestral structure and function, we searched for GnIH in agnathans, the most ancient lineage of vertebrates. We identified GnIH precursor gene and mature GnIH peptides with C-terminal QPQRF-amide or RPQRF-amide from the brain of sea lamprey. Lamprey GnIH fibers were in close proximity to GnRH-III neurons. Further, one of lamprey GnIHs stimulated the expression of lamprey GnRH-III peptide in the hypothalamus and gonadotropic hormone β mRNA expression in the pituitary. We further identified the ancestral form of GnIH, which had a C-terminal RPQRF-amide, and its receptors in amphioxus, the most basal chordate species. The amphioxus GnIH inhibited cAMP signaling in vitro. In sum, the original forms of GnIH may date back to the time of the emergence of early chordates. GnIH peptides may have had various C-terminal structures slightly different from LPXRF-amide in basal chordates, which had stimulatory and/or inhibitory functions on reproduction. The C-terminal LPXRF-amide structure and its inhibitory function on reproduction may be selected in later-evolved vertebrates, such as birds and mammals.
Highlights
Reproduction is one of the essential mechanisms for life
It became clear that the regulatory mechanism of reproduction is not as simple as it was once considered, since gonadotropininhibitory hormone (GnIH), a novel hypothalamic neuropeptide, was found to be involved in the regulation of the HPG axis (Tsutsui et al, 2000)
To investigate the evolutionary origin of gonadotropin-inhibitory hormone (GnIH), we identified the orthologous gene of GnIH and mature GnIH peptides in the brain of lamprey, one of the oldest lineage of vertebrates, Agnatha (Osugi et al, 2012)
Summary
The hypothalamic-pituitary-gonadal (HPG) axis is known as the core mechanism regulating reproduction. It became clear that the regulatory mechanism of reproduction is not as simple as it was once considered, since gonadotropininhibitory hormone (GnIH), a novel hypothalamic neuropeptide, was found to be involved in the regulation of the HPG axis (Tsutsui et al, 2000). We further identified the ancestral form of GnIH in amphioxus, the most basal chordates (Osugi et al, 2014). These studies suggest that the origin of GnIH-like peptides may date back to the time of the emergence of early chordates. Based on these new findings, this review highlights the evolution of GnIH peptide structure and its function
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