Structure, Synthesis, and Phylogeny of Kisspeptin and its Receptor - Kisspeptin Signaling in Reproductive Biology - page 12

Phylogeny of gpr54-1 and gpr54-2
It has also been generally accepted that the gene for the kisspeptin receptors, gpr54 ,
has also been duplicated before the divergence of teleosts and tetrapods, as shown in
Fig. 2.3 (see ref. [ 37 ]). Recent studies have shown by in vitro luciferase reporter
assays that both Kiss1 and Kiss2 ligands activate both Gpr54-1 and Gpr54-2, and that
these genes have been duplicated early in the vertebrate lineage [ 7 , 8 ]. Thus, in the
mammalian lineage, Kiss1 and Gpr54 are the only kisspeptin and kisspeptin receptor,
because Kiss2 and Gpr54 - 2 were lost after divergence from the monotremes.
Some studies refer to gpr54 - 1 and gpr54 - 2 as kiss1r and kiss2r in accordance
with [ 9 ] and because Gpr54-2 has relatively higher affi nity for Kiss2 in zebrafi sh.
However, because it has been clearly shown that both Kiss1 and Kiss2 bind to and
activate both Gpr54-1 and Gpr54-2 [ 3 - 5 ], and, in contrast, the one-to-one relation-
ship between kisspeptin (Kiss1 or Kiss2) and the receptor (Gpr54-1 or Gpr54-2) has
not been unequivocally demonstrated by either anatomical or physiological meth-
ods, we simply call them gpr54 - 1 and gpr54 - 2 in this chapter. We are of the opinion
that we should wait for the anatomical and/or physiological demonstration of the
projection of Kiss1/Kiss2 neurons and the distribution of kisspeptin receptors before
we can refer to them as kiss1r or kiss2r .
Figure 2.3 summarizes, as a phylogenetic tree, the expression of kiss1 / 2 and
gpr54 - 1 /- 2 in some representative species. Interestingly, gpr54 - 2 is suggested to
play more critical roles in teleosts, because some species lack gpr54 - 1 , and broader
distribution of gpr54 - 2 expressions in the brain has been reported in some teleosts.
In contrast, it is interesting that gpr54 - 2 has been lost in mammals during evolution,
and gpr54 - 1 appears to have taken its place. Although there has been no study to
systematically examine the distribution or cellular localization of gpr54 - 1 or gpr54 -
2 in the nonmammalian tetrapod brain, the inverse situation in teleosts and mam-
mals is intriguing. Likewise, it is interesting that wider variety of species in teleosts
appear to possess kiss2 compared to kiss1 . Moreover, kiss1 is lost in reptiles, while
kiss2 remains intact. Thus, except for mammals, kiss2 appears to be more widely
conserved throughout vertebrate species. However, the contribution of kiss1 or kiss2
to the central regulation of the hypothalamic-pituitary-gonadal (HPG) axis should
not be evaluated only by the existence or absence of the gene(s) in the phylogenetic
tree, because the loss of the gene can be functionally compensated for by the other
genes, especially by close relative genes.
By taking the phylogenetic tree into account, it is clear that both the genes for
ligands and receptors have been duplicated at least before the divergence of teleosts
and tetrapods. In other words, the common ancestor of teleosts and tetrapods are
considered to have possessed two ligands and two receptors. Except for the com-
plete loss of the kisspeptin system in avian species, reported in chicken and zebra-
fi nch [ 7 ], the genes for at least one ligand and one receptor remained in each
vertebrate species. The losses of genes seem to have taken place randomly, but, as
described above, there appears to be some basic rules for the gene loss by natural
selection in each branch. In the long history of vertebrate evolution, it appears that