A Small Change With a Twist Ending: A Single Residue in EGF-CFC Drives Bilaterian Asymmetry

Asymmetries 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 deuterostomes.

Automated summary

Asymmetries are crucial for the proper organization and function of organ systems. The Nodal/Smad2 pathway has been shown to play a key role in the establishment of body asymmetries in bilaterians. In this study, the orthologs of the egf-cfc gene, a master regulator of the Nodal pathway, were identified in invertebrate species, providing evidence of its presence in non-deuterostomes. The functional experiments revealed that egf-cfc does not contribute to the establishment of left-right asymmetry in gastropods, but a mutation in this gene in the common ancestor of chordates was found to induce a gain of function in LRA regulation.