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Abstract
Trichoplax adhaerens, the only known species of Placozoa is likely to be closely related to an early metazoan that preceded branching of Cnidaria and Bilateria. This animal species is surprisingly well adapted to free life in the World Ocean inhabiting tidal costal zones of oceans and seas with warm to moderate temperatures and shallow waters. The genome of T. adhaerens (sp. Grell) includes four nuclear receptors, namely orthologue of RXR (NR2B), HNF4 (NR2A), COUP-TF (NR2F) and ERR (NR3B) that show a high degree of similarity with human orthologues. In the case of RXR, the sequence identity to human RXR alpha reaches 81% in the DNA binding domain and 70% in the ligand binding domain. We show that T. adhaerens RXR (TaRXR) binds 9-cis retinoic acid (9-cis-RA) with high affinity, as well as high specificity and that exposure of T. adhaerens to 9-cis-RA regulates the expression of the putative T. adhaerens orthologue of vertebrate L-malate-NADP+ oxidoreductase (EC 1.1.1.40) which in vertebrates is regulated by a heterodimer of RXR and thyroid hormone receptor. Treatment by 9-cis-RA alters the relative expression profile of T. adhaerens nuclear receptors, suggesting the existence of natural ligands. Keeping with this, algal food composition has a profound effect on T. adhaerens growth and appearance. We show that nanomolar concentrations of 9-cis-RA interfere with T. adhaerens growth response to specific algal food and causes growth arrest. Our results uncover an endocrine-like network of nuclear receptors sensitive to 9-cis-RA in T. adhaerens and support the existence of a ligand-sensitive network of nuclear receptors at the base of metazoan evolution.
Highlights
Life on Earth began 4.1 to 3.5 billion years ago (Bell et al, 2015) with the appearance of the first unicellular organisms that subsequently evolved, in part, to multicellular lifeforms forming the kingdom Metazoa that have specialized tissues for digestion, regulation of homeostasis, locomotion, perception, analysis of the environment and reproduction.In contrast to unicellular organisms, metazoans are in need of regulatory mechanisms that provide the means of coordination between various tissues in a tight arrangement with cellular homeostasis
Our results show that T. adhaerens RXR binds 9-cis-RA with an affinity comparable to that of vertebrate and jellyfish RXRs and that T. adhaerens responds to nanomolar concentrations of 9-cis-RA with a transcriptional upregulation of the putative orthologue of a malic enzyme that is regulated by a heterodimer formed by liganded thyroid hormone receptor and RXR in vertebrates
To visualize changes in nuclear receptor expression in the absence of a reliable housekeeping gene as a reference, we considered the absolute quantity of each nuclear receptor as a percentage of the overall nuclear receptor expression and subsequently visualized the change of receptor expression by subtraction of the percentage of the control experiment
Summary
In contrast to unicellular organisms, metazoans are in need of regulatory mechanisms that provide the means of coordination between various tissues in a tight arrangement with cellular homeostasis This coordination on the level of humoral signaling includes regulation by nuclear receptors (NRs), which respond to small, mostly hydrophobic molecules, including hormones produced by specific tissues, metabolites or even molecules present in the environment and transfer these signals to the nucleus, leading to a dynamically changing but adaptive gene expression (Escriva, Bertrand & Laudet, 2004). NRs play an important role in maintaining intra- and inter-cellular functions in multicellular organisms Their overall structure is common in most nuclear receptors and consists of an A/B (N-terminal) domain, the DNA binding domain (DBD), a hinge region, the ligand binding domain (LBD) and the C-terminal domain (Kumar & Thompson, 1999; Robinson-Rechavi, Escriva Garcia & Laudet, 2003). NRs that evolved within these subfamilies show functional connections that include specialization of regulatory functions in time or cell type restriction, fortification of ancestral functions or their specific inhibition by newly evolved NRs (Escriva, Bertrand & Laudet, 2004; Kostrouchova & Kostrouch, 2015)
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