Of Retinoids and Organotins: The Evolution of the Retinoid X Receptor in Metazoa

Abstract

Nuclear receptors (NRs) are transcription factors accomplishing a multiplicity of functions, essential for organismal homeostasis. Among their numerous members, the retinoid X receptor (RXR) is a central player of the endocrine system, with a singular ability to operate as a homodimer or a heterodimer with other NRs. Additionally, RXR has been found to be a critical actor in various processes of endocrine disruption resulting from the exposure to a known class of xenobiotics termed organotins (e.g., tributyltin (TBT)), including imposex in gastropod molluscs and lipid perturbation across different metazoan lineages. Thus, given its prominent physiological and endocrine role, RXR is present in the genomes of most extant metazoan species examined to date. Here, we expand on the phylogenetic distribution of RXR across the metazoan tree of life by exploring multiple next-generation sequencing projects of protostome lineages. By addressing amino acid residue conservation in combination with cell-based functional assays, we show that RXR induction by 9-cis retinoic acid (9cisRA) and TBT is conserved in more phyla than previously described. Yet, our results highlight distinct activation efficacies and alternative modes of RXR exploitation by the organotin TBT, emphasizing the need for broader species sampling to clarify the mechanistic activation of RXR.

The Preservation of PPARγ Genome Duplicates in Some Teleost Lineages: Insights into Lipid Metabolism and Xenobiotic Exploitation

“…For instance, in the Echinodermata Paracentrotus lividus , PPARγ is unresponsive to TBT despite the conservation of H3 cysteine, whereas the cysteine-to-tyrosine substitutions observed in teleosts such as zebrafish and in the mollusk Patella depressa yield null or repressive responses, respectively [ 4 , 5 , 6 ]. Alternative modes for TBT binding have also been proposed for RXR [ 78 ]. Thus, future structural studies should address these potential alternative binding architectures.…”

Nuclear Receptors and Development of Marine Invertebrates

“…In vitro, RXRs are activated by a number of different compounds, including 9- cis -RA and fatty acids, such as docosahexaenoic acids (DHAs) [ 112 , 113 ]. Orthologs of vertebrate RXRs have been identified in most metazoan taxa, including sponges, placozoans and cnidarians, suggesting that RXRs originated at the base of the animal tree of life [ 57 , 114 ]. Lineage-specific duplications of RXR genes are rare and have so far only been reported in two lophotrochozoans: bryozoans and platyhelminths ( Figure 3 ) [ 57 ].…”

“…Orthologs of vertebrate RXRs have been identified in most metazoan taxa, including sponges, placozoans and cnidarians, suggesting that RXRs originated at the base of the animal tree of life [ 57 , 114 ]. Lineage-specific duplications of RXR genes are rare and have so far only been reported in two lophotrochozoans: bryozoans and platyhelminths ( Figure 3 ) [ 57 ]. RXR is widely expressed during development of most marine invertebrate taxa, including cnidarians, mollusks and tunicates.…”

“…Even though it is still not clear to what extent the teratogenic effects of EDCs in invertebrates are mediated by NRs, it has been shown that NRs are involved in embryonic and post-embryonic development in these animals [ 47 , 48 , 49 , 50 , 51 , 52 , 53 ]. Yet, the mechanisms at play are not necessarily conserved with vertebrates, revealing lineage-specific adaptions in both invertebrates and vertebrates [ 1 , 10 , 17 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 ]. The aim of this review is to describe and discuss the developmental functions of NRs in invertebrates, with a special focus on marine organisms, highlighting the particular importance of comparative approaches using emerging marine invertebrate models for the field of evolutionary developmental biology.…”

Retinoids in Embryonic Development

“…Contrasting the other research articles that are focused on a specific model organism, Fonseca et al explore the phylogenetic distribution of RXRs in the animal tree of life. They further survey the capacity of RXRs from different animals to bind the RA isomer 9- cis RA and the xenobiotic compound tributyltin (TBT) and find that 9- cis RA and TBT can activate RXRs from more animal phyla than initially anticipated [ 17 ].…”