Fig. 5

Proposed model for the evolution of EGF-CFC role in Metazoa. The orthologs for EGF-CFC in spiralian representatives display different amino acids on this relevant position in the EGF-like domain, whereas all representatives of Chordata and some echinoderms display a threonine. The change of amino acid in this specific position would have happened either in the ancestor of Chordata or in the ancestor of all deuterostomes (see supplementary S3, Supplementary Material online). This gave the coreceptor the ability to interact with the ligand, and regulate Pitx expression, thereby participating in the establishment of LRA. In Spiralia and its ancestor, the function of EGF-CFC would not be linked to LRA, but to gastrulation and axis determination. The regulation of LRA is proposed to be independent of the coreceptor for Spiralia. Pitx ancestral function would be related to neural specification, and it would remain as the only function of this gene in those clades that lack the ligand and coreceptor. The color filled boxes represent presence of the protein in a given clade. The gray filled boxes represent inferred hypothetical presence of the protein. The dotted line boxes represent the absence of an ortholog. X, any amino acid; T, threonine; LRA, left-right asymmetry.