Functional and evolutionary insights into vertebrate kisspeptin systems from studies of fish brain

The kiss1 gene product kisspeptin is now considered to be an essential regulator of the hypothalamic-pituitary-gonadal (HPG) axis in most vertebrate species. Recent findings in fishes are beginning to set a new stage for the kisspeptin study; the existence of paralogous kisspeptin genes as well as kisspeptin receptor (formerly called GPR54) genes has quite recently been reported in several fish and amphibian species. The fishes may provide excellent animal models for the study of general principles underlying the kisspeptin and kisspeptin receptor systems of vertebrates from the evolutionary viewpoint. Unlike placental and marsupial mammalian species mainly studied so far, many teleost species have two paralogous genes of kisspeptin, kiss1 and kiss2. Medaka, Oryzias latipes, in which kiss1 and kiss2 are expressed in distinctive hypothalamic neuron populations, is a good model system for the study of central regulation of reproduction. Here, the kiss1 system but not the kiss2 system shows expression dynamics strongly indicative of its direct involvement in the HPG axis regulation via its actions on GnRH1 neurons. On the other hand, the kiss1 gene is missing, and only kiss2 is expressed in some fish species. Also, there are some recent reports that Kiss2 peptide may be a potent regulator of reproduction in some fish species. The ancestral vertebrate probably already had two paralogous kiss genes, and their main function was the HPG axis regulation. In the species that retained both paralogues during evolution, either Kiss1 or Kiss2 predominantly retains its ability for the HPG axis regulation, while the other may assume new non-reproductive functions (neofunctionalization). Alternatively, both the paralogues may assume complementary functions in the HPG axis regulation (subfunctionalization). After the divergence of teleost and tetrapod lineages, either one of the two paralogues, or even both in birds, have been lost (degradation) or became a pseudogene (non-functionalization), but the remaining paralogue retained its original function of HPG axis regulation. The identification of multiple forms of kisspeptin receptors and the rather promiscuous ligand-receptor relationships has led to the further proposal that such promiscuousness may be the basis for the functional robustness of kisspeptin and kisspeptin receptor systems in the HPG axis regulation, when one or both paralogous genes are lost or functionally partitioned during evolution.