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Nuclear Receptor Genes: Evolution

  1. Pablo J Sáez1,
  2. Soledad Lange1,
  3. Tomas Pérez-Acle2,
  4. Gareth I Owen1

Published Online: 15 JAN 2010

DOI: 10.1002/9780470015902.a0006145.pub3

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How to Cite

Sáez, P. J., Lange, S., Pérez-Acle, T. and Owen, G. I. 2010. Nuclear Receptor Genes: Evolution. eLS. .

Author Information

  1. 1

    Pontificia Universidad Católica de Chile, Departamento de Ciencias Fisiológicas, Santiago, Chile

  2. 2

    Pontificia Universidad Católica de Chile, Departamento de Ciencias Fisiológicas and Centre for Bioinformatics, Santiago, Chile

Publication History

  1. Published Online: 15 JAN 2010

Introduction

  1. Top of page
  2. Introduction
  3. Evolutionarily Conserved Structure
  4. Nuclear Receptor Ancestor
  5. Diversification of Nuclear Receptors in the Lower Metazoa
  6. Nuclear Receptor Expansion in the Cambrian Period
  7. Steroid Hormone Receptor Evolution
  8. Continuing Evolution of Nuclear Receptors
  9. References
  10. Further Reading

The ancestor of the nuclear receptors first appeared as a single gene in the early metazoans, possibly pre-porifera, and subsequently duplicated and diversified into the current six receptor subfamilies which were already recognizable in the last common ancestor of the arthropods and chordates over 600 million years ago (mya; Figure 1). As members of the nuclear receptor (NR) superfamily acquired the ability to hetero- and homodimerize, as well as the ability to bind and be regulated by ligands, the functional complexity of these receptors increased. This exponentially increasing complexity subsequently provided a potential driving force in the evolution of higher organisms. This superfamily which includes ligand-mediated receptors along with ligandless ‘orphan’ receptors has evolved, and is still evolving, to mediate nearly every facet of metazoan life. See also Nuclear Receptor Genes

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Figure 1. (a) A schematic representation of the metazoan family tree, showing the potential branching points of the last common ancestors between each phylum. (b) The six subfamilies of the nuclear receptor (NR) superfamily. A consensus phylogenetic tree demostrating the distribution of representative nuclear receptor members in the Metazoa and their distribution into six subfamilies. This figure uses the trivial names of the NRs. For a complete list of the corresponding new nomenclature see Nuclear Receptors Committee 1999 or the Nuclear Receptor Nomenclature Home page. This phylogenetic tree was constructed using the ClustalX program v2.0 with the near-neighbour joining method. From top to bottom the accession numbers are: XP_779976, P13631, BAA25569, NP_001071806, NP_001123279, AAF57280, XP_001636937, NP_775180, CAA61534, AAL29199, XP_001619117, XP_001634258, XP_001632045, AAL29194, ACF16007, ABI97120, BAE06416, P11474, AAU88062, NP_001135406, XP_002117374, XP_001636637, XP_002117375, XP_001624292, NP_001122483, XP_001631058, AAL29201, AAL29196, XP_002109806, XP_002159396, BAE06356, AAF54774, XP_001944021, XP_001629708, AAL29200, AAF57091, XP_002154441, XP_001624815, XP_001634999, AAF52303, XP_780706, ACG76360, XP_001630385, AAP79295, XP_001630386, AAL29193, AAC80008, NP_476781, BAE06678, XP_002109459, BAF85823, AAW34268, NP_001097126, BAE06492, XP_001638550, XP_002159483, CAA61134, XP_002115810, ACA04755, CAD57002, NP_730359, ACH68437, XP_001179003, BAE06474, NP_001024953, CAA06670.

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Figure 1. (continued) (a) A schematic representation of the metazoan family tree, showing the potential branching points of the last common ancestors between each phylum. (b) The six subfamilies of the nuclear receptor (NR) superfamily. A consensus phylogenetic tree demostrating the distribution of representative nuclear receptor members in the Metazoa and their distribution into six subfamilies. This figure uses the trivial names of the NRs. For a complete list of the corresponding new nomenclature see Nuclear Receptors Committee 1999 or the Nuclear Receptor Nomenclature Home page. This phylogenetic tree was constructed using the ClustalX program v2.0 with the near-neighbour joining method. From top to bottom the accession numbers are: XP_779976, P13631, BAA25569, NP_001071806, NP_001123279, AAF57280, XP_001636937, NP_775180, CAA61534, AAL29199, XP_001619117, XP_001634258, XP_001632045, AAL29194, ACF16007, ABI97120, BAE06416, P11474, AAU88062, NP_001135406, XP_002117374, XP_001636637, XP_002117375, XP_001624292, NP_001122483, XP_001631058, AAL29201, AAL29196, XP_002109806, XP_002159396, BAE06356, AAF54774, XP_001944021, XP_001629708, AAL29200, AAF57091, XP_002154441, XP_001624815, XP_001634999, AAF52303, XP_780706, ACG76360, XP_001630385, AAP79295, XP_001630386, AAL29193, AAC80008, NP_476781, BAE06678, XP_002109459, BAF85823, AAW34268, NP_001097126, BAE06492, XP_001638550, XP_002159483, CAA61134, XP_002115810, ACA04755, CAD57002, NP_730359, ACH68437, XP_001179003, BAE06474, NP_001024953, CAA06670.

Evolutionarily Conserved Structure

  1. Top of page
  2. Introduction
  3. Evolutionarily Conserved Structure
  4. Nuclear Receptor Ancestor
  5. Diversification of Nuclear Receptors in the Lower Metazoa
  6. Nuclear Receptor Expansion in the Cambrian Period
  7. Steroid Hormone Receptor Evolution
  8. Continuing Evolution of Nuclear Receptors
  9. References
  10. Further Reading

The NR superfamily present in all living metazoans is classified not by function but by the presence of one or more conserved domains (Figure 2). Based on conserved structure the superfamily has been classically categorized into six major subfamilies (I–VI) (Figure 1b). However, with the arrival of genome sequencing, this classification may need to be revised to include potential new subfamilies which group receptors containing only one domain, contain duplicated domains and the plethora of yet to be characterized NRs which so far are confined only to the nematode lineage and diplobastic metazoans (Sluder and Maina, 2001; Wu et al., 2007; Figure 1). Classically, a canonical NR possesses five to six functional regions named A–F (Owen and Zelent, 2000; Figure 2). The most highly conserved domain within the superfamily is the C region or deoxyribonucleic acid (DNA)-binding domain (DBD) which facilitates sequence-specific interaction with the major groove of the double helix. This domain has maintained nearly 50% homology between all the superfamily members and over 90% homology between paralogous receptors (paralogous receptors are genes which have arisen by duplication within an ancestral species, for example, retinoic acid receptor alpha (RARA), retinoic acid receptor beta (RARB) and retinoic acid receptor gamma (RARG); Figure 2; also classified as NR1B1, NR1B2 and NR1B3 respectively; Nuclear Receptors Committee, 1999). As alluded to earlier, the genome of the Platyhelminthe Schistosoma mansoni contains three NRs that each contain two tandem DBDs (2DBD) (Sm2DBDα, Sm2DBDβ and Sm2DBDγ) (Wu et al., 2006). By database mining, 2DBD-containing NR genes were identified from the other flatworm species, Schmidtea mediterranea and Dugesia japonica, from mollusks (Lottia gigantean) and from arthropods (Daphnia pulex). The presence of this in three separate phylum suggest that this DBD duplication occurred in one rearrangement in NR structure took place in the one of the first protostomata species if not before (Wu et al., 2007). The second highest degree of conservation is observed in the E region or ligand-binding domain (LBD). The LBD is functionally complex and possesses subregions implicated in ligand binding, dimerization and transcriptional regulation. Although the A/B region displays no sequence conservation between different NRs, the B region has been conserved among paralogues. The D region or Hinge domain acts as a flexible linking region between the adjacent C and E regions as well as containing the nuclear localization signal. The terminal regions of the Hinge domain have been conserved among various NRs, particularly between paralogues, whereas the central region has not been subjected to the same evolutionary pressure. Although conservation is high among paralogous receptors, such as the retinoid acid X-receptors (RXRs), only 4% homology in this region is observed across the six subfamilies represented in Figure 1b. Although absent in many receptors, an extreme poorly conserved C-terminal F domain is present which can confer ligand and coactivator specificity (Figure 2).

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Figure 2. Structural homology of the retinoic acid receptor (RAR). Alignment of the human RAR paralogues, alpha (a), beta (b) and gamma (g), and the RAR isolated from the urochordate Polyandrocarpa misakiensis (accession number BAA25569). The boxes represent the location of functional domains within the nuclear receptor. Numerical representation given below the alignment relates to the homology for each domain between the human RAR paralogues and between the three paralogues and the urochordate RAR. This global multiple sequence alignment was generated using the ClustalX program v2.0.

Conservation in sequence and structure is often correlated with placing of an NR into a specific subfamily. For example, if it is assumed that heterodimerization with the RXRs only arose once in NR evolution, the majority of the heterodimerization partners should be confined to the same family, which is exactly what is observed with subfamily I (Figure 1). However, no correlation exists between subfamily localization and ligand-binding ability or specificity (Escriva et al., 2000). This suggests that independent acquisition of ligand binding has occurred several times in the course of metazoan evolution. To date, only the retinoic acid X receptor (RXR) and the Hepatocyte Nuclear Factor 4 (HNF4) have been detected in the demosponge Suberites domuncula (Table 1) and are thus phylogenetically the earliest nuclear hormone receptors identified. The presence of these NRs in the sponge, a member of the oldest extant metazoan phylum, Porifera, suggests that this superfamily may have played a fundamental role in metazoan evolution (Wiens et al., 2003). It is currently unknown if the sponge RXR and HNF4 can bind 9-cis-retinoic acid and fatty acids, respectively, as has been reported in higher metazoans. The earliest report to date of an NR capable of ligand binding is the jellyfish RXR (jfRXR, Table 1; Tripedalia cystophora, Figure 1b) which can bind the ligand 9-cis-retinoic acid with a higher affinity than mammalian RXRs (Kostrouch et al., 1998). The presence of a ligand-binding RXR in the Cnidaria places the acquisition of ligand binding close to the base of the metazoan tree, which is a lot earlier than perhaps anticipated.

Table 1. Nuclear receptors in pre-bilaterians phyla
SourceOrganismTrivial nameReceptor typeSubfamilyAccession numberReference
  1. Note: Nuclear receptors from Porifera, Placozoa and Cnidaria are listed and compared against other receptors from metazoan phyla.

SpongeSuberites domunculasdRXRRXRIICAD57002Wiens et al. 2003
SpongeAmphimedon queenslandicaAmqHNF4HNF4IIACA04755Larroux et al. 2006
PlacozoaTrichoplax adhaerensTriadERRERRIIIXP_002117375Srivastava et al. 2008
PlacozoaTrichoplax adhaerensTriadRXRRXRIIXP_002109459Srivastava et al. 2008
PlacozoaTrichoplax adhaerensTriadHNF4HNF4IIXM_002115774Srivastava et al. 2008
PlacozoaTrichoplax adhaerensTriadCOUPCOUPIIXM_002109770Srivastava et al. 2008
HydrozoayuHydra magnipapillataTaillessIIXP_002154441Unpublished NCBI submission
HydrozoaHydra magnipapillataCOUPIIXP_002159396Unpublished NCBI submission
HydrozoaHydra magnipapillataHNF-4IIXP_002159483Unpublished NCBI submission
HydrozoaHydra vulgarisHvCOUPCOUPIIAAB68702.1Escriva et al. 1997
JellyfishTripedalia cystophorajfRXRRXRIIAAC80008Kostrouch et al. 1998
CoralMontipora verrucosaMvCOUPCOUPIIAF254813Tarrant et al. (unpublished)
CoralAcropora milleporaAmNR1TaillessIIAAL29193Grasso et al. 2001
CoralAcropora milleporaAmNR2DHR38/NGF1bIVAAL29194Grasso et al. 2001
CoralAcropora milleporaAmNR3COUP-like LBDIIAAL29195Grasso et al. 2001
CoralAcropora milleporaAmNR4 ATR2/4IIAAL29196Grasso et al. 2001
CoralAcropora milleporaAmNR4 BTR2/4IIAAL29197Grasso et al. 2001
CoralAcropora milleporaAmNR6DHR38/NGF1bIVAAL29199Grasso et al. 2001
CoralAcropora milleporaAmNR7COUPIIAAL29200Grasso et al. 2001
CoralAcropora milleporaAmNR8TR2/4IIAAL29201Grasso et al. 2001
Sea anemoneNematostella vectensisNRIVXP_001636937Putnam et al. 2007
Sea anemoneNematostella vectensisAmNR6IVXP_001619117Putnam et al. 2007
Sea anemoneNematostella vectensisAmNR6IVXP_001634258Putnam et al. 2007
Sea anemoneNematostella vectensisAmNR2IVXP_001632045Putnam et al. 2007
Sea anemoneNematostella vectensisNRIIIXP_001636637Putnam et al. 2007
Sea anemoneNematostella vectensisNRIIXP_001624292Putnam et al. 2007
Sea anemoneNematostella vectensisNRIIXP_001631058Putnam et al. 2007
Sea anemoneNematostella vectensisTaillessIIXP_001634999Putnam et al. 2007
Sea anemoneNematostella vectensisTaillessIIXP_001624815Putnam et al. 2007
Sea anemoneNematostella vectensisTaillessIIXP_001630385Putnam et al. 2007
Sea anemoneNematostella vectensisNRIIXP_001629708Putnam et al. 2007
Sea anemoneNematostella vectensisHNF4IIXP_001638550Putnam et al. 2007

Nuclear Receptor Ancestor

  1. Top of page
  2. Introduction
  3. Evolutionarily Conserved Structure
  4. Nuclear Receptor Ancestor
  5. Diversification of Nuclear Receptors in the Lower Metazoa
  6. Nuclear Receptor Expansion in the Cambrian Period
  7. Steroid Hormone Receptor Evolution
  8. Continuing Evolution of Nuclear Receptors
  9. References
  10. Further Reading

Nucleic acid sequence databases have demonstrated the presence of NRs only within the metazoan lineage and not in plants, fungi, algae or protozoa (Escriva et al., 2004). Although NRs contain well-conserved domains, such as domains C and E, there is no convincing evidence that suggests that genes encoding such proteins provided building blocks in the construction of the ancestral NR. The analysis of the deduced protein obtained from the full-length clone of the demosponge RXR suggests that the first NR contained both the domains now classified as C and E domains (Wiens et al., 2003). Although NRs have demonstrated transcriptional activation ability through protein–protein interactions and nongenomic mechanisms, the high conservation of the DBD suggests that the primary role of the NR was in DNA binding. The ancestral NR may have mediated transcription via monomeric binding and in a ligand-independent fashion. Genomic analysis and in vitro studies from yeast demonstrate that the basal transcriptional machinery, including coregulators and histone acetyltransferases, were already present before the appearance of the NR (Owen and Zelent, 2000). The rapid incorporation and diversification of the newly arrived ancestral NR in the Metazoa can therefore be understood.

The assumption that the NR superfamily arose from a single ancestral gene makes the classification of these genes into specific subfamilies impossible (as this is the ancestor of all subfamilies). The two subfamily II NRs currently reported in sponge may contain the structures nearest to the initial receptors that diversified into the six subfamilies present in triploblasts today (Figure 1b and Table 1). The observation that sponge HNF4 and RXR group together and not with the central HNF4 and RXR clades (see Figure 1b) may tantalizingly suggest that these two genes arose from direct duplication in an extinct early metazoan. However, this assumption may change completely with the continued sequencing and reclassification of lower metazoan genomes.

Diversification of Nuclear Receptors in the Lower Metazoa

  1. Top of page
  2. Introduction
  3. Evolutionarily Conserved Structure
  4. Nuclear Receptor Ancestor
  5. Diversification of Nuclear Receptors in the Lower Metazoa
  6. Nuclear Receptor Expansion in the Cambrian Period
  7. Steroid Hormone Receptor Evolution
  8. Continuing Evolution of Nuclear Receptors
  9. References
  10. Further Reading

The identity of the most primitive extant (living) metazoan is controversial. The general consensus places Porifera before Cnidaria; however, the placement of Placozoa is hotly debated and may constitute the first metazoan or the first triploblast (Schierwater et al., 2008; Srivastava et al., 2008). These characterized branches of the metazoan tree demonstrate 2 NRs in living sponges (Porifera) (Figure 1a and Table 1), 4 NRs in the Placozoan Trichoplax and the 21 NRs currently (middle of 2009) available for the phylum Cnidaria. This provides strong evidence that the superfamily originated from a common ancestor and then diversified, a conclusion aided by the observation that some cnidarian receptors possess a DBD that is characteristic of one NR subfamily, whereas the LBD of this same receptor is characteristic of a separate subfamily. See also Placozoa

A major fork in the metazoan tree, after Porifera, Placazoa and Cnidaria, saw the protostomes diverge from the deuterostomes (Figure 3). At the time of this division, NRs had already diversified into the six major subfamilies recognized today (Figure 1b). The path from the protodeuterostome ancestor to Arthropoda indicates divergence of the Platyhelminthes (flatworms), Mollusca (snails, clams), Annelida (segmented worms) and Nematoda (roundworms) (Figure 1a). Along with the NRs containing two DNA-binding domains aforementioned, this protostome lineage further demonstrates examples of NRs that have diversified. The cnidarian jfRXR has higher homology with the human RXR − 78% homology in the DBD and an astonishing 79% homology in the LBD (Kostrouch et al., 1998) – than with the fruitfly RXR orthologue, ultraspiracle (USP). The arthropod ixodid tick possesses two RXR paralogues which have a DBD closer to that of USP yet have LBD closer to vertebrate RXRs. Neither USP, which has acquired the ability to bind juvenile hormone, nor the tick RXRs are thought to bind the ligand 9-cis-retinoic acid, whereas jfRXR is capable of binding this compound with higher affinity than the mammalian RXR.

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Figure 3. Retinoic acid receptor (RAR) and retinoic acid X-receptor (RXR) in different metazoans. The presence of assayed RAR and RXR genes is shown in coloured boxes. The information given in this figure is based on BLAST search results, which have been verified by phylogenetic analyses. Modified with permission from Campo-Paysaa et al. 2008.

Comparison of the nematode (Caenorhabditis elegans), human and fruitfly (Drosophila melanogaster) genomes demonstrates 284 predicted NRs in the nematode, which is six times more than the 52 receptors identified in humans and over 10 times more than the 18 genes present in the relatively close fruitfly (Maglich et al., 2003; Magner and Antebi, 2008). In the nematode, the majority of these NRs appear to have arisen through proliferation and diversification of one chromosome. Fewer than 20 of the receptors from Caenorhabditis elegans possess orthologues with the six subfamilies that are present in the arthropods and vertebrates (to date, only subfamily III members are not represented in Caenorhabditis elegans) and thus the majority of nematode receptors are from phylogenetically unconserved groupings that are still in the process of being identified (Gissendanner et al., 2004; Sluder and Maina, 2001).

The earliest chordates, defined by the presence of a notochord at some stage in their life history, are placed within the subphylum Urochordata (Figure 3). This subphylum, which includes the tunicates, sea squirts and salps, contains the NR denominated NR-1, which is related to, and maybe the direct ancestor of, the thyroid hormone receptor (THR) (Figure 1 and Figure 3). Although NR-1 is 86% and 58% homologous in its DNA and LBDs respectively to the human THR, it does not appear to bind thyroid hormone and does not possess activation function 2 (AF-2). This presents a paradoxical observation in that the Urochordata synthesizes thyroid hormone that is involved in morphogenesis while possessing a potential thyroid hormone receptor, without the possession of ligand-binding ability. This may provide insight into the evolution of nuclear receptors as ligand-activated transcription factors, where the ligand predates the receptor. Despite the presence of orthologues of RAR and RXR in several protostomata (Albalat and Canestro, 2009; Figure 3), in the Urochordata we also see an RAR homologue which shows 92% and 71% homology in the DNA and LBD respectively with vertebrate RAR receptor paralogues. Interestingly, a member of a genus of Urochordata (Oikopleura) has been shown to have lost RAR expression and the retinoic acid signalling which mediates chordate development (Figure 3; Holland and Garcia-Fernandez, 1996). The subphylum Cephalochordata, best known for its well-studied member the Amphioxus, is regarded as the nearest extant phylum before the genome expansion (represented as 1–4 on Figure 1a) in the Cambrian period that gave rise to the higher vertebrates. Thus this subphylum may possess the last common ancestor of the RXR and RAR before the duplication events which led to the presence of the alpha, beta and gamma paralogues of each receptor in higher vertebrates. See also Analysis of the Amphioxus Genome, and Urochordata (Tunicates)

Nuclear Receptor Expansion in the Cambrian Period

  1. Top of page
  2. Introduction
  3. Evolutionarily Conserved Structure
  4. Nuclear Receptor Ancestor
  5. Diversification of Nuclear Receptors in the Lower Metazoa
  6. Nuclear Receptor Expansion in the Cambrian Period
  7. Steroid Hormone Receptor Evolution
  8. Continuing Evolution of Nuclear Receptors
  9. References
  10. Further Reading

Although the NR superfamily was diverse at the time of the protostome–deuterostome split, the superfamily went through a substantial increase in number during the Cambrian period around 544–505 mya. The path taken between the early Craniata and the rise of jawed vertebrates has left two intermediate extant subphyla – Hyperotreti and Hyperoartia as represented by the hagfishes and the lampreys, respectively. During this geological period it is postulated that a craniate ancestor underwent a series of duplications to give rise to a genome that possessed two, three or four paralogues of NR genes (denoted as 1–4 on Figure 1a). One or more paralogues are found for most NRs. A strong example of a potential quadruplication of an ancient receptor, as is seen in other gene families such as members of the homeobox cluster, is demonstrated by the steroid hormone receptors from NR subfamily III. However, it is most likely that after this quadruplication several genes have been lost to leave only two members (e.g. ERs alpha and beta) or three members as demonstrated by the retinoic acid receptors alpha, beta and gamma in the human (Figure 2). See also Evolutionary Developmental Biology: Hox Gene Evolution

Steroid Hormone Receptor Evolution

  1. Top of page
  2. Introduction
  3. Evolutionarily Conserved Structure
  4. Nuclear Receptor Ancestor
  5. Diversification of Nuclear Receptors in the Lower Metazoa
  6. Nuclear Receptor Expansion in the Cambrian Period
  7. Steroid Hormone Receptor Evolution
  8. Continuing Evolution of Nuclear Receptors
  9. References
  10. Further Reading

The steroid hormone receptors, which in the human comprise six members, include the oestrogen receptors (ER) alpha and beta, and receptors for progesterone (PR), androgen (AR), glucocorticoid (GR) and mineralocorticoid (MR). These six members may have arisen in the chordate lineage from an early ER which had diversified from an ancient ERR present in the bilaterians or a primitive triploblast. The steroid hormone receptors and ERRs are members of subfamily III with potentially the earliest identified member being an ERR now being isolated from both the Placozoa and the Cnidaria (Table 1 and Figure 1). ERR homologues have also been identified in the arthropod fruitfly Urochordata, Cephalochordata, hagfish and lamprey (Escriva et al., 1997; Figure 1). Sequence comparison and the detection of an ER in the protostome lineage Annelida demonstrates that before the last common ancestor of protosomes and deterosomes an ancient ERR duplicated and resulting modifications gave rise to a receptor capable of binding oestrogen as a ligand (ER; Figure 4). To date no further evidence of this receptor has been identified until the Cephalochordate, where it is possible that this receptor duplicated again to give rise to the sequence denominated PR/CR, that after two rounds of genome-level duplication, generated the PR, GR, MR and AR cluster present today in jawed vertebrates. These four receptors maintained the ability to bind steroid molecules, acquiring only minor modifications in ligand specificity. In line with the genome duplication theory, the PR/CR ancestor was probably present before the rise of the Craniata. An intermediate PR-related sequence has been detected in the earliest extant craniate, the hagfish, although whether this partial sequence represents the original member of this clad or the hagfish version of the lamprey PR or corticoid receptor (CR) cannot be determined. During the genome duplication events in the Cambrian period, the PR/CR ancestor duplicated to give rise to a progestin receptor and a CR which have been detected in the lamprey (Thornton, 2001). The lamprey is believed to represent an intermediate species in the genome expansion process; thus in the last common ancestor of lamprey and jawed vertebrates, the PR and CR duplicated again to give to the AR and the MR, respectively. The same duplication events, which quadruplicated the PR/CR ancestor, most likely gave rise to paralogous ERs (ER alpha and beta) and to three paralogues of the ERR (ERR 1, 2 and 3) within subfamily III. Despite being depicted in Figure 4 as two whole-genome duplication events, this was probably not the case; however, this progress had been completed before the appearance of the teleosts (bony fish). Although, no further duplication events giving rise to functional receptors have taken place in the lineage leading to terrestrial vertebrates, the ancestor of many of the modern fish experienced a second round of genome amplification with the appearance of a third ER paralogue (ER gamma) and the presence of new AR and PR paralogues (duplication represented as ‘D’ in Figure 1a and in Figure 4). Interestingly, in the teleost fish, which are not believed to possess the mineralocorticoid ligand aldosterone, both salt balance and metabolic activities are controlled by glucocorticoids. In mammals the liganded MR and GR share these functions and in accordance with this there are major structural differences in the GR and MR present in the teleost lineage in comparison to terrestrial vertebrates.

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Figure 4. Model of NR subfamily III evolution. Steroid hormone receptors originated from a duplication of an ancient ER. This hypothetical receptor represented as PR/CR ancestor, duplicated and gave rise to the PR and CR which are present in the lamprey and then duplicated once more to give the PR, GR, MR and AR present in terrestrial vertebrates. A further genome-level duplication event occurred within the teleost lineage. ERR refers to oestrogen-related receptor; ER, oestrogen receptor; PR, progesterone receptor; CR, corticoid receptor; AR, androgen receptor; GR, glucocorticoid receptor and MR, mineralocorticoid receptor.

Continuing Evolution of Nuclear Receptors

  1. Top of page
  2. Introduction
  3. Evolutionarily Conserved Structure
  4. Nuclear Receptor Ancestor
  5. Diversification of Nuclear Receptors in the Lower Metazoa
  6. Nuclear Receptor Expansion in the Cambrian Period
  7. Steroid Hormone Receptor Evolution
  8. Continuing Evolution of Nuclear Receptors
  9. References
  10. Further Reading

NRs are still evolving. The genome sequencing projects and specific studies have revealed the presence of new NR sequences which are given the domination psuedogenes (Zhang et al., 2008). In the human these gene products relate to the farnesoid X receptor (FXR) and HNF4 gamma, along with the presence of two ERR psuedogenes (Maglich et al., 2001; Maglich et al., 2003; Zhang et al., 2008). Analysis of these ERR psuedogenes suggests that the duplication occurred less that 38 mya. Of interest is that in the chimpanzee, which as expected shares a high similarity to humans in pseudogenes, one of the ERR pseudogenes has since been lost. Analysis of the mouse genome demonstrates unique pseudogenes of the LRH1 nuclear receptor that are not present in primates. These pseudogenes may well be future functional NR superfamily members waiting for evolutionary pressure to incorporate them into the ever increasingly complex metazoan regulatory network. See also Nuclear Receptor Genes, and Nuclear Receptors and Disease

End Notes
  1. Based in part on the previous version of this Encyclopedia of Life Sciences (ELS) article, Nuclear Receptor Genes: Evolution by Gareth I Owen.

References

  1. Top of page
  2. Introduction
  3. Evolutionarily Conserved Structure
  4. Nuclear Receptor Ancestor
  5. Diversification of Nuclear Receptors in the Lower Metazoa
  6. Nuclear Receptor Expansion in the Cambrian Period
  7. Steroid Hormone Receptor Evolution
  8. Continuing Evolution of Nuclear Receptors
  9. References
  10. Further Reading

Further Reading

  1. Top of page
  2. Introduction
  3. Evolutionarily Conserved Structure
  4. Nuclear Receptor Ancestor
  5. Diversification of Nuclear Receptors in the Lower Metazoa
  6. Nuclear Receptor Expansion in the Cambrian Period
  7. Steroid Hormone Receptor Evolution
  8. Continuing Evolution of Nuclear Receptors
  9. References
  10. Further Reading