The control of reproductive physiology and behavior by gonadotropin-inhibitory hormone

Abstract

Gonadotropin-releasing hormone (GnRH) controls the reproductive physiology and behavior of vertebrates by stimulating synthesis and release of gonadotropin from the pituitary gland. In 2000, another hypothalamic neuropeptide, gonadotropin-inhibitory hormone (GnIH), was discovered in quail and found to be an inhibiting factor for gonadotropin release. GnIH homologs are present in the brains of vertebrates, including birds, mammals, amphibians, and fish. These peptides, categorized as RF amide-related peptides (RFRPs), possess a characteristic LPXRF-amide (X = L or Q) motif at their C-termini. GnIH/RFRP precursor mRNA encodes a polypeptide that is possibly cleaved into three mature peptides in birds and two in mammals. The names of these peptides are GnIH, GnIH-related peptide-1 (GnIH-RP-1) and GnIH-RP-2 in birds, and RFRP-1 and RFRP-3 in mammals. GnIH/RFRP is synthesized in neurons of the paraventricular nucleus of the hypothalamus in birds and the dorsomedial hypothalamic area in mammals. GnIH neurons project to the median eminence, thus providing a functional neuroanatomical infrastructure to regulate anterior pituitary function. In quail, GnIH inhibits gonadal activity by decreasing synthesis and release of gonadotropin. The widespread distribution of GnIH/RFRP immunoreactive fibers in all animals tested suggests various actions within the brain. In accordance, GnIH/RFRP receptor mRNA is also expressed widely in the brain and the pituitary. GnIH/RFRP immunoreactive axon terminals are in probable contact with GnRH neurons in birds and mammals, and we recently demonstrated expression of GnIH receptor mRNA in GnRH-I and GnRH-II neurons in European starlings. Thus, GnIH/RFRP may also inhibit gonadotropin synthesis and release by inhibiting GnRH neurons in addition to having direct actions on the pituitary gland. Intracerebroventricular administration of GnIH/RFRP further inhibits reproductive behaviors in songbirds and rodents, possibly via direct actions on the GnRH system. The expression of GnIH/RFRP is regulated by melatonin which is an internal indicator of day length in vertebrates. Stress stimuli also regulate the expression of GnIH/RFRP in songbirds and rodents. Accordingly, GnIH/RFRP may serve as a transducer of environmental information and social interactions into endogenous physiology and behavior of the animal. Recently, it was shown that GnIH/RFRP and its receptor are also expressed in the gonads of birds, rodents and primates. In sum, the existing data suggest that GnIH/RFRP is an important mediator of reproductive function acting at the level of the brain, pituitary, and the gonad in birds and mammals.

Fig. 1

Alignment of GnIH precursor polypeptides in representative birds and mammals. Characteristic LPXRF (X = L or Q) motif at the C-termini for RFRPs followed by glycine as an amidation signal and arginine or lysine as endoproteolytic basic amino acids are underlined. The possible RFRP/GnIH peptide sequences with possible endoproteolytic basic amino acids at both ends are shown in bold.

Fig. 2

Alignment of GnIH precursor polypeptides in several birds, mammals, and fish. Characteristic LPXRF (X = L or Q) motif at the C-termini for RFRPs followed by glycine as an amidation signal and arginine or lysine as endoproteolytic basic amino acids are shown in bold. LPLRS-amide or LPLRL-amide sequences encoded in the GnIH/RFRP-2 position of the precursor polypeptide of chimpanzee (Pan troglodytes), human (Homo sapiens), and cattle (Bos Taurus) are also shown in bold. Coturnix japonica: Japanese quail; Gallus gallus: red jungle fowl; Sturnus vulgaris: European starling; Zonotrichia leucophrys: white-crowned sparrow; Equus caballus: horse; Mus musculus: house mouse; Rattus norvegicus: Norway rat; Carassius auratus: goldfish; and Danio rerio: zebrafish.

Fig. 3

2D representation of the human RFRP receptor (GPR147). The transmembrane region was predicted using SOSUI (Hirokawa et al. 1998). Glycosylation and disulfide bridge sites were predicted by GPCRDB (Horn et al. 1998).

Fig. 4

Possible control mechanisms of reproductive physiology and behavior by GnIH (RFRP) and GnRH in birds and mammals. Stimulatory and inhibitory control mechanisms of the reproductive physiology and behavior regulate the production of their offspring. GnRH: gonadotropin-releasing hormone; GnIH: gonadotropin-inhibitory hormone; LH: luteinizing hormone; FSH: follicle-stimulating hormone.