A small change with a twist ending: a single residue in EGF-CFC drives bilaterian asymmetry

Abstract

This is a pre-copyedited, author-produced PDF of an article accepted for publication in Molecular biology and evolution following peer review. The version of record Molecular biology and evolution 40.2 (2023): msac270 is available online at: https://academic.oup.com/search-results?page=1&q=10.1093%2Fmolbev%2Fmsac270&fl_SiteID=191&SearchSourceType=1&allJournals=1Asymmetries are essential for proper organization and function of organ systems. Genetic studies in bilaterians have shown signaling through the Nodal/Smad2 pathway plays a key, conserved role in the establishment of body asymmetries. Although the main molecular players in the network for the establishment of left-right asymmetry (LRA) have been deeply described in deuterostomes, little is known about the regulation of Nodal signaling in spiralians. Here, we identified orthologs of the egf-cfc gene, a master regulator of the Nodal pathway in vertebrates, in several invertebrate species, which includes the first evidence of its presence in non-deuterostomes. Our functional experiments indicate that despite being present, egf-cfc does not play a role in the establishment of LRA in gastropods. However, experiments in zebrafish suggest that a single amino acid mutation in the egf-cfc gene in at least the common ancestor of chordates was the necessary step to induce a gain of function in LRA regulation. This study shows that the egf-cfc gene likely appeared in the ancestors of deuterostomes and "protostomes", before being adopted as a mechanism to regulate the Nodal pathway and the establishment of LRA in some lineages of deuterostome