Decrypting the phylogenetics history of EGF-CFC proteins Cripto and Cryptic

EGF-CFC proteins are obligate coreceptors for Nodal signaling and are thus required for gastrulation and left-right patterning. Species with multiple family members show evidence of specialization. For example, mouse Cripto is required for gastrulation, whereas Cryptic is involved in left-right patterning. However, the members of the family across model organisms have little sequence conservation beyond the EGF-CFC domain, posing challenges for determining their evolutionary history and functional conservation. In this study we outline the evolutionary history of the EGF-CFC family of proteins. We traced the EGF-CFC gene family from a single gene in the deuterostome ancestor through its expansion and functional specialization in tetrapods, and subsequent gene loss and translocation in eutherian mammals. Mouse Cripto and Cryptic, zebrafish Tdgf1, and all three Xenopus EGF-CFC genes (Tdgf1, Tdgf1.2 and Cripto.3) and are all descendants of the ancestral Tdgf1 gene. We propose that subsequent to the family expansion in tetrapods, Tdgf1B (Xenopus Tdgf1.2) acquired specialization in the left-right patterning cascade, and after its translocation in eutherians to a different chromosomal location, Cfc1/Cryptic has maintained that specialization.