Abstract
BackgroundThe origin of nuclear receptors (NRs) and the question whether the ancestral NR was a liganded or an unliganded transcription factor has been recently debated. To obtain insight into the evolution of the ligand binding ability of estrogen receptors (ER), we comparatively characterized the ER from the protochordate amphioxus (Branchiostoma floridae), and the ER from lamprey (Petromyzon marinus), a basal vertebrate.ResultsExtensive phylogenetic studies as well as signature analysis allowed us to confirm that the amphioxus ER (amphiER) and the lamprey ER (lampER) belong to the ER group. LampER behaves as a "classical" vertebrate ER, as it binds to specific DNA Estrogen Responsive Elements (EREs), and is activated by estradiol (E2), the classical ER natural ligand. In contrast, we found that although amphiER binds EREs, it is unable to bind E2 and to activate transcription in response to E2. Among the 7 natural and synthetic ER ligands tested as well as a large repertoire of 14 cholesterol derivatives, only Bisphenol A (an endocrine disruptor with estrogenic activity) bound to amphiER, suggesting that a ligand binding pocket exists within the receptor. Parsimony analysis considering all available ER sequences suggest that the ancestral ER was not able to bind E2 and that this ability evolved specifically in the vertebrate lineage. This result does not support a previous analysis based on ancestral sequence reconstruction that proposed the ancestral steroid receptor to bind estradiol. We show that biased taxonomic sampling can alter the calculation of ancestral sequence and that the previous result might stem from a high proportion of vertebrate ERs in the dataset used to compute the ancestral sequence.ConclusionTaken together, our results highlight the importance of comparative experimental approaches vs ancestral reconstructions for the evolutionary study of endocrine systems: comparative analysis of extant ERs suggests that the ancestral ER did not bind estradiol and that it gained the ability to be regulated by estradiol specifically in the vertebrate lineage, before lamprey split.
Highlights
The origin of nuclear receptors (NRs) and the question whether the ancestral nuclear hormone receptor (NR) was a liganded or an unliganded transcription factor has been recently debated
The obtained cDNA [GenBank: ACF16007] is 2118 bp long and encodes a 705 aa long putative protein (Figure 1) that harbors the classical features of an estrogen receptors (ER) with the 5 main functional domains (Figure 2A), among which a highly conserved DNA binding domain (DBD) and a less conserved ligand binding domain (LBD)
The three other domains, namely the A/B region in the N-terminal part, the hinge between DBD and ligand-binding domain (LBD), and the short C-terminal end of the protein, are more divergent, which is a general pattern for NRs [2] (Figure 2A)
Summary
The origin of nuclear receptors (NRs) and the question whether the ancestral NR was a liganded or an unliganded transcription factor has been recently debated. The nuclear hormone receptor (NR) superfamily includes ligand dependent transcription factors that play a central role in various physiological processes as diverse as reproduction, development, and control of homeostasis [1,2]. They share a common structural organization and exhibit a highly conserved DNA binding domain (DBD) and a moderately conserved ligand-binding domain (LBD). Some members of this superfamily are liganded receptors (24 among the 48 genes encoding NRs in the human genome) but many lack identified ligand and are called "orphan" [3]. The existence of such orphan receptors with physiological or developmental activities constitutes both a major challenge for understanding nuclear receptor evolution and a potential opportunity for pharmacology [1]
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