Gonadotropin-Releasing Hormone and Adipokinetic Hormone Signaling Systems Share a Common Evolutionary Origin

Neuropeptides and protein hormones are ancient molecules that mediate cell-to-cell communication. The whole genome sequence from the red flour beetle Tribolium castaneum, along with those from other insect species, provides an opportunity to study the evolution of the genes encoding neuropeptide and protein hormones. We identified 41 of these genes in the Tribolium genome by using a combination of bioinformatic and peptidomic approaches. These genes encode >80 mature neuropeptides and protein hormones, 49 peptides of which were experimentally identified by peptidomics of the central nervous system and other neuroendocrine organs. Twenty-three genes have orthologs in Drosophila melanogaster: Sixteen genes in five different groups are likely the result of recent gene expansions during beetle evolution. These five groups contain peptides related to antidiuretic factor-b (ADF-b), CRF-like diuretic hormone (DH37 and DH47 of Tribolium), adipokinetic hormone (AKH), eclosion hormone, and insulin-like peptide. In addition, we found a gene encoding an arginine-vasopressin-like (AVPL) peptide and one for its receptor. Both genes occur only in Tribolium and not in other holometabolous insects with a sequenced genome. The presence of many additional osmoregulatory peptides in Tribolium agrees well with its ability to live in very dry surroundings. In contrast to these extra genes, there are at least nine neuropeptide genes missing in Tribolium, including the genes encoding the prepropeptides for corazonin, kinin, and allatostatin-A. The cognate receptor genes for these three peptides also appear to be absent in the Tribolium genome. Our analysis of Tribolium indicates that, during insect evolution, genes for neuropeptides and protein hormones are often duplicated or lost.

GnRH is the pivotal hypothalamic hormone regulating reproduction. Over 20 forms of the decapeptide have been identified in which the NH2- and COOH-terminal sequences, which are essential for receptor binding and activation, are conserved. In mammals, there are two forms, GnRH I which regulates gonadotropin and GnRH II which appears to be a neuromodulator and stimulates sexual behaviour. GnRHs also occur in reproductive tissues and tumours in which a paracrine/autocrine role is postulated. GnRH agonists and antagonists are now extensively used to treat hormone-dependent diseases, in assisted conception and have promise as novel contraceptives. Non-peptide orally-active GnRH antagonists have been recently developed and may increase the flexibility and range of utility. As with GnRH, GnRH receptors have undergone co-ordinated gene duplications such that cognate receptor subtypes for respective ligands exist in most vertebrates. Interestingly, in man and some other mammals (e.g. chimp, sheep and bovine) the Type II GnRH receptor has been silenced. However, GnRH I and GnRH II still appear to have distinct roles in signalling differentially through the Type I receptor (ligand-selective-signalling) to have different downstream effects. The ligand-receptor interactions and receptor conformational changes involved in receptor activation have been partly delineated. Together, these findings are setting the scene for generating novel selective GnRH analogues with potential for wider and more specific application.

Gonadotropin-releasing hormone (GnRH) plays a central role in vertebrate reproduction. The evolutionary origin of this neuropeptide and its receptor is not obvious, but the advent of genomics makes it possible to examine the roots of GnRH and delve deeper into its ancestral relationships. New peptide sequences identified in invertebrates from annelids to tunicates reveal GnRH-like peptides of 10-12 amino acids. Structural conservation suggests homology between the 15 known invertebrate peptides and the 15 known vertebrate GnRHs. The functions of the invertebrate GnRH-like peptides are not necessarily related to reproduction. We suggest that structurally related families of invertebrate peptides including corazonin and adipokinetic hormone (AKH) form a superfamily of neuropeptides with the GnRH family. GnRH receptors have also been identified in invertebrates from annelids to tunicates suggesting that the origin of GnRH and its receptor extends deep in evolution to the origin of bilaterian animals. To resolve the relationship of invertebrate and vertebrate receptors, we conducted large-scale phylogenetic analysis using maximum likelihood. The data support a superfamily that includes GnRH, AKH and corazonin receptors derived from both published sequences and unpublished gene model predictions. Closely related to the GnRHR superfamily is the vasopressin/oxytocin superfamily of receptors. Phylogenetic analysis suggests a shared ancestry with deep roots. A functional role for GnRH in vertebrates or invertebrates leads to questions about the evolutionary origin of the pituitary. Our analysis suggests a functioning pituitary was the result of genomic duplications in early vertebrates. Copyright © 2010 Elsevier Inc. All rights reserved.