Neuroendocrinology of reproduction: Is gonadotropin-releasing hormone (GnRH) dispensable?

Abstract

Gonadotropin releasing hormone (GnRH) is a highly conserved neuroendocrine decapeptide that is essential for the onset of puberty and the maintenance of the reproductive state. First identified in mammals, the GnRH signaling pathway is found in all classes of vertebrates; homologues of GnRH have also been identified in invertebrates. In addition to its role as a hypothalamic releasing hormone, GnRH has multiple functions including modulating neural activity within specific regions of the brain. These various functions are mediated by multiple isoforms, which are expressed at diverse locations within the central nervous system. Here we discuss the GnRH signaling pathways in light of new reports that reveal that some vertebrate genomes lack GnRH1. Not only do other isoforms of GnRH not compensate for this gene loss, but elements upstream of GnRH1, including kisspeptins, appear to also be dispensable. We discuss routes that may compensate for the loss of the GnRH1 pathway.

Keywords: Domestication; Evolution; Gene loss; Genome; GnIH; Kisspeptin; Synteny; Zebrafish.

Figure 1.. Structure of the vertebrate hypothalamus and description of gnrh/GnRH containing cells in the adult zebrafish brain.

(A, B) Schematic diagram of a lateral view of the mouse (A) and the zebrafish (B) brain. In mammals (A), the GnRH cells (red) project to the median eminence, a highly vascularized connection to the pituitary. In teleosts (B), the neurohypophysis (NeH) is reduced and the GnRH cells make neural connections with the pituitary. (C-E) gnrh2 and gnrh3 expression detected by in situ hybridization in the midbrain (C), and terminal nerve (D, d1, d2) and ventral telencephalon (D, d3) [133] In contrast, GnRH cells in the parvocellular nucleus of the hypothalamus can be detected only by immunohistochemistry (E from [62]). There are no convincing data supporting cellular expression of any gnrh gene in the parvocellular nucleus of the adult zebrafish. Abbreviations: Arc, arcuate nucleus; Hv, ventral zone of periventricular hypothalamus; Hc, caudal zone of periventricular hypothalamus; (red asterisk), neurosecretory preoptic area; ME, median eminence; NeH, neurohypophysis; OB, olfactory bulb; PVN, paraventricular nucleus; SON, supraoptic nucleus; TeO, tectum opticum; VMN, ventromedial nucleus. (A, B modified from [3], [4]).

Figure 2.. Genomic rearrangements in the syntenic region of GnRH1 shows a loss of gnrh1 in zebrafish.

(A) Analysis of conserved syntenies in the region of the gnrh1 gene reveals an inversion of the kctd9 gene in zebrafish relative to the other species, suggesting a re-arrangement in this region (see text for details). Human ankrd is boxed in grey because it is located on a separate chromosome. (B, C) Genes controlling sex determination in zebrafish have been altered by domestication. In wild-caught zebrafish (B), the majority of fish heterozygous at the Z locus (Chr4*/Chr4) become females (solid arrow). Animals with two copies of the Z locus (light blue band) on chromosome 4 (Chr4*/Chr4*) become males. Under specific conditions Chr4*/Chr4 animals can become neomales (dashed arrow, see text). In contrast, laboratory strains AB and TU (C) have lost this locus (Chr4*) on chromosome 4 and the population exists as Chr4/Chr4 where both females and neomales are generated (solid yellow arrows) albeit often in skewed sex-ratios.

Figure 3.. Loss of gnrh1 pre-dates the domestication of zebrafish.

(A-D) neither lab strains (A) nor wild-caught (B) zebrafish contain the gnrh1 gene. In wild-caught zebrafish this interval contains small deletions not present in the lab stains (indicated as gaps in the schematic). In contrast to zebrafish, medaka contains gnrh1 (C). Similar to zebrafish, the cavefish Astyanax mexicanus lacks the gnrh1 gene (D). (E) Simplified lineage tree of fishes. Similarly to zebrafish (Danio rerio, Order Cypriniformes, Family Cyprinidae; panels C and D), the genome of the cavefish (Astyanax mexicanus, Order Characiformes, Family Characidae; panel B) lacks gnrh1 (E adapted from [134])

Figure 4.. Potential alternative pathways replacing GnRH1 signaling in zebrafish.

(A) Cells containing GnRH-Inhibitory hormone (GnIH) (black) are shown relative to the populations of cells with which GnIH might interact: GnRH1 (red), GnRH2 (green), and GnRH3 (blue), and Kisspeptins (orange). (B) GnIH signaling pathways in the brain pituitary axis. In zebrafish, the loss of gnrh1 and loss-of-function mutations in gnrh2, gnrh3, kiss1, and kiss2, do not result in infertility, thus suggesting a potential direct interaction of GnIH on the pituitary gonadotropes (red arrow). This unusual loss of signaling may be due to intense selective pressures (red box: gene loss + domestication) (A modified from [134]; B modified from [122]). (C) The recently discovered reproductive peptide, phoenixin (PNX), can stimulate kisspeptin (purple) and GnRH (blue) release in hypothalamic cell lines. In intact animals PNX can stimulate LH release from the hypothalamus (green cell with solid arrows) although the exact details have yet to be uncovered. PNX is conserved in fish and is a candidate peptide for hypothalamic-pituitary interactions in zebrafish (C from [135]).