The search for non‐chordate retinoic acid signaling: lessons from chordates

Abstract

Signaling by retinoic acid (RA) is an important pathway in the development and homeostasis of vertebrate and invertebrate chordates, with a critical role in mesoderm patterning. Classical studies on the distribution of nuclear receptors of animals suggested that the family of RA receptors (RARs/NR1B) was restricted to chordates, while the family of RA X receptors (RXR/NR2B) was distributed from cnidarians to chordates. However, the accumulation of data from genome projects and studies in non-model species is questioning this traditional view. Here we discuss the evidence for non-chordate RA signaling systems in the light of recent advances in our understanding of carotene (pro-Vitamin A) metabolism and of the identification of potential RARs and members of the NR1 family in echinoderms and lophotrochozoan trematodes, respectively. We conclude, as have others before (Bertrand et al., 2004. Mol Biol Evol 21(10):1923-1937), that signaling by RA is more likely an ancestral feature of bilaterians than a chordate innovation.

Retinoic acid signaling in development: Tissue‐specific functions and evolutionary origins

“…During animal development, RA is synthesized from retinol in two steps of NAD-dependent oxidation, each catalyzed by different families of enzymes ( Fig. 1b) (reviewed in Simões-Costa et al, 2008). After cellular uptake of ingested retinol by a system involving retinol binding protein (RBP) and the transmembrane protein STRA6 (Kawaguchi et al, 2007), the first step of RA synthesis is the reversible oxidation of retinol to retinal by enzymes of two different families: Only the major actors of the pathway (enzymes involved in retinoid synthesis, degradation, binding, and signaling) are shown.…”

“…amphioxus and different tunicate species) provided evidence for roles of RA during development of all chordates (Cañ-estro and Postlethwait, 2007;De Bernardi et al, 1994;Denucé, 1991;Hinman and Degnan, 1998;Holland and Holland, 1996;Katsuyama et al, 1995). Moreover, recent studies have suggested a possible presence of this pathway in other deuterostomes: bioinformatic analyses have revealed rar, cyp26, and raldh homologs in the genome of the sea urchin Strongylocentrotus purpuratus and raldh and cyp26 homologs in EST sequences from the hemichordate Saccoglossus kowalevskii (Cañestro et al, 2006;Howard-Ashby et al, 2006;Marlétaz et al, 2006;Ollikainen et al, 2006;Simões-Costa et al, 2008).…”

“…After it became clear that RA signaling and function is not limited to vertebrates, RA signaling was considered to be chordate-specific, until some very recent analyses identified molecular components of the RA pathway in non-chordate deuterostomes, such as echinoderms and hemichordates (Cañestro et al, 2006;Howard-Ashby et al, 2006;Marlétaz et al, 2006;Ollikainen et al, 2006;Simões-Costa et al, 2008). In this review, we use these recent findings as a basis to discuss our current understanding of the evolution of the RA signaling cascade.…”

Retinoic Acid and the Development of the Endoderm

“…A significant role for RA signaling in the development of endoderm might appear somewhat surprising because endoderm is a germ layer of all multi-layered embryos, whereas the RA signaling system has often been described as a signaling system that has arisen during chordate evolution [3,4]. There is now, however, evidence that homologues of enzymes and receptors necessary for RA signaling exist in different invertebrates [5][6][7], but it is still not clear as to whether or not these homologues function in an analogous manner. If in fact they have alternate functions, then retinoic acid signaling may be an adaption that occurred during evolution and unique to the chordates.…”

Chordate origins and evolution

“…Campo-Paysaa et al (2008) discuss the evolution of our views on retinoic acid (RA) signaling across animals. First considered a vertebrate-specific and then a chordate-specific system operating in the elaboration of the Anterior-Posterior axis, RA signaling is now increasingly perceived as an ancestral system that dates back to the bilaterian ancestor, owing to the characterization of some of its key players in the genomes of an echinoderm and one hemichordate, among deuterostomes, as well of a gastropod mollusk and an annelid, among protostomes (Campo-Paysaa et al 2008;Cañestro et al, 2006;Howard-Ashby et al 2006;Marlétaz et al, 2006a;Simões-Costa et al, 2008 and references therein; see also Albalat and Cañestro, 2008). Campo-Paysaa et al speculate that RA signaling may have played a role in neurite outgrowth and neuronal survival during development of the bilaterian ancestor, a role echoed by related actions of the RA in vertebrates and mollusks, but that it was subsequently lost in the lineage leading to ecdysozoan protostomes.…”