Abstract
It is essential to discover novel neuropeptides that regulate the functions of pituitary, brain and peripheral secretory glands for the progress of neuroendocrinology. Gonadotropin-releasing hormone (GnRH), a hypothalamic neuropeptide stimulating gonadotropin release was isolated and its structure was determined by Schally's and Guillemin's groups at the beginning of the 1970s. It was subsequently shown that GnRH is highly conserved among vertebrates. GnRH was assumed the sole hypothalamic neuropeptide that regulates gonadotropin release in vertebrates based on extensive studies of GnRH over the following three decades. However, in 2000, Tsutsui's group isolated and determined the structure of a novel hypothalamic neuropeptide, which inhibits gonadotropin release, in quail, an avian species, and named it gonadotropin-inhibitory hormone (GnIH). Following studies by Tsutsui's group demonstrated that GnIH is highly conserved among vertebrates, from humans to agnathans, and acts as a key neuropeptide inhibiting reproduction. Intensive research on GnIH demonstrated that GnIH inhibits gonadotropin synthesis and release by acting on gonadotropes and GnRH neurons via GPR147 in birds and mammals. Fish GnIH also regulates gonadotropin release according to its reproductive condition, indicating the conserved role of GnIH in the regulation of the hypothalamic-pituitary-gonadal (HPG) axis in vertebrates. Therefore, we can now say that GnRH is not the only hypothalamic neuropeptide controlling vertebrate reproduction. In addition, recent studies by Tsutsui's group demonstrated that GnIH acts in the brain to regulate behaviors, including reproductive behavior. The 18 years of GnIH research with leading laboratories in the world have significantly advanced our knowledge of the neuroendocrine control mechanism of reproductive physiology and behavior as well as interactions of the HPG, hypothalamic-pituitary-adrenal and hypothalamic-pituitary-thyroid axes. This review describes how GnIH was discovered and GnIH research progressed in this new research era of reproductive neuroendocrinology.
Highlights
A newresearch field in endocrinology was created by the discovery of neurosecretion, which was named neuroendocrinology
Harris [3] hypothesized that hypothalamic neurons that terminate at the median eminence (ME) may secrete neurohormones from the ME into the hypophysial portal system to regulate the secretion of anterior pituitary hormones, such as thyroid stimulating hormone (TSH), gonadotropins, i.e., luteinizing hormone (LH) and follicle-stimulating hormone (FSH), growth hormone (GH) and adrenocorticotropic hormone (ACTH)
Based on the morphology of hypothalamic gonadotropin-inhibitory hormone (GnIH) neurons, Osugi et al [71] analyzed the biological action of lamprey GnIHs on lamprey gonadotropin-releasing hormone (GnRH) and gonadotropin β subunit expressions and found that lamprey GnIH increases lamprey GnRH3 and gonadotropin β subunit expressions [71]. These findings indicate that GnIH exists in the brain of lamprey, which is the oldest lineage of vertebrates and GnIH stimulates the expression of gonadotropin β in the pituitary by acting on GnRH3 neurons [71]
Summary
A newresearch field in endocrinology was created by the discovery of neurosecretion, which was named neuroendocrinology. Schally’s and Guillemin’s groups confirmed this seminal hypothesis by the discovery of important neurohormones, including thyrotropin-releasing hormone (TRH) [4, 5], gonadotropin-releasing hormone (GnRH) [6, 7] and growth hormone-inhibiting hormone (somatostatin) [8], in the brain of mammals. Subsequent studies conducted by Tsutsui’s group demonstrated that GnIH is highly conserved among vertebrates from agnathans to humans, acting as an important neurohormone that inhibits vertebrate reproduction [for reviews, see [14,15,16,17,18,19,20,21,22,23,24,25,26,27]]. This review provides a broad overview of the unity and diversity of GnIH structure and biological action and molecular evolution of GnIH in vertebrates
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