A single amino acid change drives left- right asymmetry in Bilateria

Abstract

Asymmetries are essential for proper organization and function of organ systems. Genetic studies in deuterostomes have shown signaling through the Nodal/Smad2 pathway plays a key, conserved role in the establishment of body asymmetries. While Nodal signaling is required for the establishment of left-right asymmetry (LRA) across bilaterian species, 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, 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 LRA in gastropods. However, experiments in zebrafish suggest that a single amino acid mutation in the egf-cfc gene in the deuterostome common ancestor was the necessary step in inducing a gain-of-function in LRA regulation. This study shows that that the egf-cfc gene likely appeared in the bilaterian stem lineage, before being adopted as a master mechanism to regulate the Nodal pathway and the establishment of LRA in deuterostomes.