The Evolutionary History of Ephs and Ephrins: Toward Multicellular Organisms

Eph receptor (Eph) and ephrin signaling regulate fundamental developmental processes through both forward and reverse signaling triggered upon cell–cell contact. In vertebrates, they are both classified into classes A and B, and some representatives have been identified in many metazoan groups, where their expression and functions have been well studied. We have extended previous phylogenetic analyses and examined the presence of Eph and ephrins in the tree of life to determine their origin and evolution. We have found that 1) premetazoan choanoflagellates may already have rudimental Eph/ephrin signaling as they have an Eph-/ephrin-like pair and homologs of downstream-signaling genes; 2) both forward- and reverse-downstream signaling might already occur in Porifera since sponges have most genes involved in these types of signaling; 3) the nonvertebrate metazoan Eph is a type-B receptor that can bind ephrins regardless of their membrane-anchoring structure, glycosylphosphatidylinositol, or transmembrane; 4) Eph/ephrin cross-class binding is specific to Gnathostomata; and 5) kinase-dead Eph receptors can be traced back to Gnathostomata. We conclude that Eph/ephrin signaling is of older origin than previously believed. We also examined the presence of protein domains associated with functional characteristics and the appearance and conservation of downstream-signaling pathways to understand the original and derived functions of Ephs and ephrins. We find that the evolutionary history of these gene families points to an ancestral function in cell–cell interactions that could contribute to the emergence of multicellularity and, in particular, to the required segregation of cell populations.
This work was supported by grants from the Spanish Ministries of Economy and Competitiveness (BFU2014-53128-R) and of Science, Innovation and Universities (RTI2018-096501-B-I00), Generalitat Valenciana (PROMETEO 2017/150) and the European Research Council (ERC AdG 322694) to M.A.N., who also acknowledges financial support from the Spanish State Research Agency (AEI), through BFU and RTI grants as above plus the “Severo Ochoa” Programme for Centres of Excellence in R&D (SEV-2017-0273). The first three grants (BFU, RTI and PROM) are cofinanced by the European Regional Development Fund, ERDF. D.G.W. was supported by the Francis Crick Institute, which receives its core funding from Cancer Research UK (FC001217), the UK Medical Research Council (FC001217), and the Wellcome Trust (FC001217).