Evolutionary diversification of retinoic acid signaling


Evolutionary diversification of retinoic acid signaling in deuterostomes: insights from sea urchins, amphioxus and lampreys

Retinoic acid (RA) is an important morphogen, which is synthesized endogenously from vitamin A. Within a target cell, RA binds to two nuclear receptors, the retinoic acid receptor (RAR) and the retinoid X receptor (RXR), which together form heterodimers. The binding of RA to RAR activates the ligand-dependent transcription factor function of the RAR/RXR heterodimer, which ultimately leads to the initiation of target gene transcription.
RA signaling was long thought to be vertebrate-specific, but studies in invertebrate chordates have revealed conserved roles for RA throughout the chordate phylum. Outside the chordate lineage, though, evidence for functional roles of RA and of the RAR/RXR heterodimer becomes much scarcer. Although members of our team have identified genes encoding orthologs of the basic vertebrate components for synthesis (RALDH) and degradation (CYP26) of endogenous RA and for RAR and RXR in xenambulacrarians (such as hemichordates and echinoderms) and lophotrochozoans (such as annelids and mollusks), extensive experimental evidence for RA functions in these organisms is still lacking.
To obtain insights into the evolutionary diversification of RA signaling, we are currently characterizing the developmental functions of key components of the RA signaling pathway (RAR, RXR, RALDH and CYP26) from sea urchins, amphioxus and lampreys (Fig. 1) using classical embryological experiments (e.g. injection-based studies, pharmacology, gene and protein expression analyses). In parallel, we are assessing, which genes are targeted, directly or indirectly, by the RAR/RXR heterodimer in these animals, using a combination of transcriptomic and genomic approaches. In amphioxus, we have already been able to show that anterior hox genes (such as hox1 and hox3) are direct targets of RA signaling and are required for RA-dependent anteroposterior patterning of the central nervous system, the ectoderm and the endoderm (Fig. 2). Through comparison of the results obtained from our three models, the ultimate goal of this project is to retrace the evolutionary diversification of the RA signaling network in deuterostomes.


Figure 1. Simplified phylogeny of metazoan animals (modified from Campo-Paysaa et al., 2008, Genesis, 46:640-656).


Figure 2. Working model for structure and functions of the retinoic acid (RA) signaling cascade in the developing amphioxus embryo (modified from Koop et al., 2010, Dev. Biol., 338:98-106).

Michael Schubert - 26/09/17