Identification of Aldh1a, Cyp26 and RAR orthologs in protostomes pushes back the retinoic acid genetic machinery in evolutionary time to the bilaterian ancestor.

In vertebrates, retinoic acid (RA) is an important morphogenetic signal that controls embryonic development, as well as organ homeostasis in adults. RA action depends on the function of the RA-genetic machinery, which includes a metabolic module and a signaling module. The metabolic module regulates the spatiotemporal distribution of RA by the combined action of the RA-synthesizing Aldh1a enzymes, and the RA-degrading Cyp26 enzymes. The signaling module includes members of the nuclear hormone receptors family RAR and RXR, and controls the transcriptional state of RA-target genes. RA-signaling has been described primarily in chordates, but the recent finding of elements of the RA-genetic machinery in non-chordate deuterostomes has changed our perspective on the evolutionary origin of this morphogenetic signal, challenging previous assumptions that related the invention of the RA-genetic machinery with the origin of the chordate body plan. To illuminate the evolutionary origin of the RA machinery we have conducted an extensive survey of Aldh1a, Cyp26 and RAR orthologs in genomic databases of 13 non-deuterostome metazoans. Our results show for the first time the presence of Aldh1a, Cyp26 and RAR in protostomes, which implies that the components of the RA machinery may be ancient elements of animal genomes, already present in the last common ancestor of bilaterians. Interestingly, our data also reveal that independent losses of the RA toolkit have occurred multiple times during animal evolution, which may have been relevant for the evolution and developmental diversity of the current metazoan lineages.