Oikopleura dioica Alcohol Dehydrogenase Class 3 Provides New Insights into the Evolution of Retinoic Acid Synthesis in Chordates

Abstract

Enzymes that synthesize retinoic acid (RA) constitute the first level of regulation of RA action. In vertebrates, enzymes of the medium-chain alcohol dehydrogenase (MDR-Adh) family catalyze the first step of the RA synthetic pathway by oxidizing retinol. Among MDR-Adh enzymes, Adh3 is the only member present in non-vertebrates, and whether Adh3 is actually involved in RA biosynthesis remains uncertain. Here, we investigate the MDR-Adh family in Oikopleura dioica, a urochordate representing the sister group to vertebrates. Oikopleura is of special interest because it has lost the classical RA role in development, which relaxed evolutionary constraints to preserve the RA-genetic machinery, leading to the loss of RA-system components. The hypothesis that Adh3 plays a role in RA synthesis predicts that the relaxation of selection in Oikopleura should have led to the loss of Adh3, or changes in residues related to retinol oxidation. The hypothesis also predicts changes in the expression pattern of Oikopleura Adh3 compared to other chordates that preserved RA-signaling. Our results, however, revealed the presence of a highly conserved Adh3 gene in Oikopleura, with no significant changes in functional residues. Our results also revealed that the Oikopleura Adh3 expression remains unchanged in comparison to other non-vertebrate chordates, restricted to specific compartments of the digestive system. Because Adh3 has been highly conserved in an animal that has dismantled the RA system, we conclude that Adh3 preservation is not due to a conserved role in RA synthesis. Thereby, if Adh3 plays a role in RA synthesis in vertebrates, it might be a lineage-specific neofunctionalization.

Diatom bloom-derived biotoxins cause aberrant development and gene expression in the appendicularian chordate Oikopleura dioica

“…To test if DD upregulates defensome genes during O. dioica development, we have analyzed the expression pattern of four defensome genes—three previously described dehydrogenase genes Adh3 51 , Aldh2 52 , and Aldh8 42 , and a here newly described glutathione-related gene (Glutamate-cysteine ligase modifier subunit; Gclm )—in six developmental stages from eight-cell stage to late hatchling of DMSO-control and DD-treated embryos at mild concentrations (e.g., 0.1 µg mL −1 ) (Fig. 5).…”

Evolution of Retinoid and Steroid Signaling: Vertebrate Diversification from an Amphioxus Perspective

“…S2, Supplementary Material online) (Cañestro et al 2002; reviewed in Gonzàlez-Duarte and Albalat 2005). Biochemically, amphioxus Adh3 is similar to vertebrate Adh3 (Cañestro et al 2000; Godoy et al 2006) suggesting that the enzyme activities of Adh1 and Adh4 were vertebrate innovations (Cañestro et al 2003, 2010).…”

The role of S-nitrosoglutathione reductase (GSNOR) in human disease and therapy

“…Studies have shown that ADH5 −/− null mice exhibit reduced retinoic acid production (Molotkov et al, 2002), and the presence of ADH5 transcript in human fetal lungs correlates with a decrease in the presence of retinol (Coste and Labbe, 2011). Ultimately, the exact nature of relationship between GSNOR and retinol is still under investigation (Boleda et al, 1993; Cañestro et al, 2010; Gonzàlez-Duarte and Albalat, 2005). …”