Retention and Silencing of Prepro-GnRH-II and Type II GnRH Receptor Genes in Mammals

Abstract

The decapeptide hypothalamic-pituitary gonadotrophin-releasing hormone (GnRH)-I and the type I GnRH receptor drive the reproductive hormonal cascade in mammals by stimulating synthesis and secretion of luteinising hormone (LH) and follicle stimulating hormone (FSH). Mammals possess a second GnRH system composed of a related hormone, GnRH-II (differing from GnRH-I by three amino acid residues), and the type II GnRH receptor. In many mammalian species, one or both of the GnRH-II system genes are disrupted or deleted, rendering their products non-functional. This includes humans who possess a gene encoding GnRH-II but lack a functional type II GnRH receptor. Here we examined the genes encoding prepro-GnRH-II (GnRH2) and the type II GnRH receptor (GnRHR2) in more than 20 mammalian species, encompassing 10 orders, to determine whether they encode functional proteins. The structural organisation of both genes in most mammalian genome sequence assemblies was poorly annotated or incompletely described. Our findings show significant variation in the DNA sequence conservation and functional status of each gene, even between closely related species. Prepro-GnRH-II was functionally compromised in 12/22 species and the type II GnRH receptor gene was disrupted in 14/22 species. Retention of large sections of each gene in most mammalian genomes suggests that mammalian ancestors had a functional GnRH-II system. Gene disruptions were due to a spectrum of mutations which must have occurred independently after the evolutionary divergence of mammals from ancestral animals. The genetic information will be useful for understanding the physiological role of the GnRH-II system and establishing animal models for functional studies.

Contribution of Chicken GnRH-II and Lamprey GnRH-III on Gonadotropin Secretion

“…Although there is evidence that the type II GnRHR may mediate behavioral effects of cGnRH-II in the Musk shrew (Kauffman et al, 2005), a functional type II GnRHR has not been reported (Stewart et al, 2009). Nevertheless, ICV infusion of cGnRH-II but not mGnRH stimulated sexual behavior in nutritionally challenged female musk shrews (Temple et al, 2003).…”

“…In the mature male Zebra finch (Taeniopygia guttata) the number of cGnRH-II neurons is significantly reduced during the non-breeding season as compared with the breeding season (Perfito et al, 2011 (Kauffman and Rissman, 2004a). However, this information is questionable due to the lack of a functional cGnRH-II peptide and the lack of a functional type II GnRHR in mice (Stewart et al, 2009). Among primates, the rhesus monkey (Macaca mulatta), is one of the few species studied to date that posses a functional cGnRH-II peptide and type II GnRHR (Stewart et al, 2009).…”

“…However, this information is questionable due to the lack of a functional cGnRH-II peptide and the lack of a functional type II GnRHR in mice (Stewart et al, 2009). Among primates, the rhesus monkey (Macaca mulatta), is one of the few species studied to date that posses a functional cGnRH-II peptide and type II GnRHR (Stewart et al, 2009). In these species, cGnRH-II is expressed in the hypothalamic median eminence (Urbanski et al, 1999), and has the ability to stimulate gonadotropin secretion (Lescheid et al, 1997).…”

“…As noted above, few primate species are known to possess a functional cGnRH-II peptide and associated type II GnRH receptor. For instance, in the Chimpanzee (Pan troglodytes) the genes encoding the cGnRH-II peptide and the type II GnRH receptor contains a premature stop codon (Ikemoto and Park, 2006;Stewart et al, 2009); therefore there is a disruption of the ligand and the receptor. Information on regard to the GnRH-II system obtained in the rhesus monkey should not be generalized to other primate species.…”

“…In the Musk shrew (Suncus murinus), cGnRH-II was identified by HPLC and radioimmunoassay (RIA), and the presence of a functional peptide subsequently reported (Dellovade et al, 1993;Rissman and Li, 1998;Stewart et al, 2009). Although there is evidence that the type II GnRHR may mediate behavioral effects of cGnRH-II in the Musk shrew (Kauffman et al, 2005), a functional type II GnRHR has not been reported (Stewart et al, 2009).…”