While agnathans appear to have reduced their Ednr repertoire
While agnathans appear to have reduced their Ednr repertoire to the Ednra gene (that may have been amplified in the Arctic lamprey), gnathostomes in general have been relatively inert to Ednr gene loss. Strikingly, the only Ednr gene that has been lost repeatedly is EdnrB2 (lost in therian mammals, reduced to one gene after the TGD in clupeocephalan teleosts, and then completely lost in zebrafish; Fig. 7). It will be interesting to functionally analyze why this endothelin receptor seems to be more dispensable than EdnrA and EdnrB1. Thus far, EdnrB2 has been functionally associated only with pigment cell migration and certain pattern developments in non-mammalian vertebrates (see e.g., Kawasaki-Nishihara et al., 2011, Nitzan et al., 2013, Pla et al., 2005) and might thus have become dispensable in the mammalian lineage. The significance of the ednrB2 loss in zebrafish also remains unclear, but could be related to the absence of the leucophore pigment cell type in zebrafish (Braasch et al., 2009).
The relationships among gnathostome Ednrs have been difficult to establish. There are three possibilities: (EdnrA (EdnrB1 EdnrB2)), (EdnrB1 (EdnrA EdnrB2)), or (EdnrB2 (EdnrA EdnrB1)). Rooting Ednr phylogenies with the amphioxus Ednr-like sequence or more distantly related GPCRs lead to inconclusive answers towards Ednr receptor relationships due to the extensive divergence of these outgroups from the Ednrs (Fig. 4A) (Braasch et al., 2009, Hyndman et al., 2009, Kuraku et al., 2010). In addition, phylogenies of multigene Cy5 RNA receptor that are part of the Ednr paralogons and that were duplicated during VGD1/2 along with the Ednr genes (Pou4f, Spry, Slain) also give contradictory results (Braasch et al., 2009). Based on the unresolved trichotomy of vertebrate Ednr genes, Hyndman et al. (2009) suggested to use the more neutral name EdnrC instead of EdnrB2 for the third endothelin receptor gene. The established relationships of the four linked Parahox paralogons (Siegel et al., 2007), however, support the (EdnrA (EdnrB1 EdnrB2)) topology with the fourth, lost Ednr being the VGD2 paralog of EdnrA (Fig. 7) (Braasch et al., 2009). Thus, EdnrB2 appears to be a legitimate name for the third Ednr receptor, a view that is further supported by the more pronounced sequence, pharmacological, and functional similarity of EdnrB2 to EdnrB (see Lecoin et al., 1998 and below), which hence should be named EdnrB1 (Braasch et al., 2009).
Evolution of vertebrate Edn ligands and endothelin receptor functions
Outlook Although the endothelin system and endothelin receptors have been studied in detail in the last 25years, a lot of questions remain regarding their functionality, interaction partners, and pharmacology (Watts, 2010). Furthermore, the availability of new genome assemblies from a multitude of vertebrate lineages highlights the diversity of endothelin system components among vertebrates. From an evolutionary point of view, the functional analysis of endothelin receptors from amphioxus, lampreys and cartilaginous fish will be important to shed new light onto the origin and early functional divergence of the endothelin system in vertebrates. Studying the endothelin system in spotted gar will help to understand the impact of the teleost genome duplication on the diversification of endothelin signaling in teleost fish. Teleost fish, particularly zebrafish and medaka, are becoming increasingly important to model human development, physiology, and disease, for example in large-scale drug screening approaches, and genome assemblies of other ‘evolutionary fish models’ for human diseases are in close reach (Schartl, 2013). Endothelin ligand–receptor interactions, however, remain understudied outside of mammals. It will therefore be important to study the functional spectrum of the endothelin system in these species to increase the predictive value of non-mammalian vertebrate models for human diseases related to the endothelin system.