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.