All About Retinoid X Receptors (RXR)

Compounds to Modulate Retinoid X Receptors

All About Retinoid X Receptors (RXR)

Compounds to Modulate Retinoid X Receptors


The human retinoid X receptors (RXRs) function as transcriptional regulators, often in partnership with members of a larger nuclear receptor family of transcription factors. RXR agonists have been shown to modulate RXR transcription and activate or repress various biological pathways and effect therapeutic results for various conditions.

There are a few RXR agonists that are known such as CD3254, Bexarotene, Bexarotene analogs, and LGD100268. Bexarotene (Targretin®) is one of the more recognized compounds and is used to treat cutaneous T-cell lymphoma (as well as off label to treat other types of cancer).

Recent research may show significant potential in its use for treatment of Alzheimer's disease.

However, Bexarotene treatment has some side effects, namely hypothyroidism, hyperlipidemia, and cutaneous toxicity, which may be due to its activation of RXR in several different tissues.

Researchers at Arizona State University have developed a portfolio of RXR agonists, which are more potent analogs and derivatives of Bexarotene, CD3254, LGD100268 and Tamibarotene.

These analogs have a higher selectivity for the retinoid X receptor versus the retinoic acid receptor (RAR) and can be uncoupled from drastic lipid changes and thyroid axis variations.

Additionally, in astrocytes and microglia, the Bexarotene analogs increase expression of ApoE and highly lipidated HDLs, which then promote clearance of amyloid beta in the brain.

These new analogs may provide viable and efficacious alternatives treatment options for cancer, Alzheimer's disease (AD), Parkinson's disease (PD), schizophrenia, and other neurodegenerative diseases. Further, animal testing suggests that the improved PK and triglyceride profiles make these compounds compelling therapeutic candidates.

Potential Applications

•       Anti-cancer treatment

o  CTCL, colon, breast, lung, pancreatic, skin, ovarian, bladder, kidney, head and neck cancers, leukemia and others

•       May be useful in treatment of AD & other neurodegenerative diseases

•       May be useful in treatment of RXR-pathway related diseases

•       May be useful in treatment of diseases associated with dopamine deficiency

o  PD, schizophrenia, depression, and other psychotic disorders

•       May be useful in treatment of non-insulin dependent diabetes mellitus

Benefits and Advantages

•       Several analogs demonstrate higher affinity/activation for RXR than Bexarotene

•       Higher efficacies/potency/specificity may allow for lower doses thus alleviating some side effects

•       Improved side effects than parent compounds

•       May stimulate gene expression better

•       Some compounds may be less toxic than parent compounds and produce statistically lower triglyceride levels

•       Improved PK characteristics

For more information about the inventor(s) and their research, please see
Dr. Wagner’s directory webpage     
Dr. Marshall’s laboratory webpage     
Dr. Jurutka’s department webpage     


Retinoid X Receptor Agonists Upregulate Genes Responsible for the Biosynthesis of All-Trans-Retinoic Acid in Human Epidermis

All About Retinoid X Receptors (RXR)

UAB30 is an RXR selective agonist that has been shown to have potential cancer chemopreventive properties. Due to high efficacy and low toxicity, it is currently being evaluated in human Phase I clinical trials by the National Cancer Institute. While UAB30 shows promise as a low toxicity chemopreventive drug, the mechanism of its action is not well understood.

In this study, we investigated the effects of UAB30 on gene expression in human organotypic skin raft cultures and mouse epidermis. The results of this study indicate that treatment with UAB30 results in upregulation of genes responsible for the uptake and metabolism of all-trans-retinol to all-trans-retinoic acid (ATRA), the natural agonist of RAR nuclear receptors.

Consistent with the increased expression of these genes, the steady-state levels of ATRA are elevated in human skin rafts. In ultraviolet B (UVB) irradiated mouse skin, the expression of ATRA target genes is found to be reduced. A reduced expression of ATRA sensitive genes is also observed in epidermis of mouse models of UVB-induced squamous cell carcinoma and basal cell carcinomas.

However, treatment of mouse skin with UAB30 prior to UVB irradiation prevents the UVB-induced decrease in expression of some of the ATRA-responsive genes.

Considering its positive effects on ATRA signaling in the epidermis and its low toxicity, UAB30 could be used as a chemoprophylactic agent in the treatment of non-melanoma skin cancer, particularly in organ transplant recipients and other high risk populations.

Citation: Wu L, Chaudhary SC, Atigadda VR, Belyaeva OV, Harville SR, Elmets CA, et al. (2016) Retinoid X Receptor Agonists Upregulate Genes Responsible for the Biosynthesis of All-Trans-Retinoic Acid in Human Epidermis. PLoS ONE 11(4): e0153556.

Editor: Michael Schubert, Laboratoire de Biologie du Développement de Villefranche-sur-Mer, FRANCE

Received: November 26, 2015; Accepted: March 31, 2016; Published: April 14, 2016

Copyright: © 2016 Wu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: All relevant data are within the paper and its Supporting Information files.

Funding: This work was supported by the National Institutes of Health Grants AA12153 (N. Y. K.), P30AR050948 (N. Y. K. and C. A. E.), P30CA013148 (C. A. E.), CA138998 (M. A.), and P50 CA089019 (D.D.M.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist.

All-trans-retinoic acid (ATRA) is a highly potent derivative of vitamin A that is required for virtually all essential physiological processes and functions because of its involvement in transcriptional regulation of over 530 different genes [1–3].

ATRA exerts its actions by serving as an activating ligand of nuclear retinoic acid receptors (RARα-γ (NR1B1-3)), which form heterodimers with retinoid X receptors (RXRα-γ (NR2B1-3)) [4].

In addition to RARs, RXRs can heterodimerize with numerous other nuclear receptors, including vitamin D receptor (VDR (NR1I1)), thyroid hormone receptor (TR (NR1A1-2)), liver X receptor (LXR (NR1H1-2)), and peroxisome proliferator-activated receptor (PPAR (NR1C1-3)). In heterodimers with permissive partners (e.g.

, PPAR and LXR), RXR can be activated by RXR agonists in the absence of the ligand of the partner, and when both partners are activated, they act in an additive or synergistic manner.

In contrast, in conditionally permissive RXR/RAR heterodimers, RAR and RXR agonists together can have a greater effect on gene transcription than the RAR agonist alone, but the ligand-dependent transcriptional activity of RXR appears “subordinated” to the binding of ATRA to its RAR partner [5]; hence, the cellular levels of ATRA are critically important for the activation of RXR/RAR signaling.

As reviewed in detail previously [6], the concentration of ATRA in the cells is tightly controlled by the enzymes responsible for its biosynthesis and degradation.

ATRA is produced from all-trans-retinol in two oxidative steps: first, retinol is oxidized to retinaldehyde by retinol dehydrogenases, and then retinaldehyde is oxidized to ATRA by retinaldehyde dehydrogenases [6].

The first step is reversible and is controlled by the opposing activities of retinol dehydrogenase(s) and retinaldehyde reductase(s) [6].

A recent study demonstrated that the retinol dehydrogenase 10 (RDH10, SDR16C4) and the ATRA-inducible retinaldehyde reductase DHRS3 (dehydrogenase/reductase 3, SDR16C1) mutually activate each other [7], indicating that the rate of ATRA biosynthesis is regulated via a sophisticated mechanism, possibly involving RDH10/DHRS3 protein-protein interactions. The levels of ATRA are also controlled via ATRA-inducible cytochrome P450 enzymes (e.g., CYP26A1 and CYP26B1), which inactivate ATRA by hydroxylation [6].

The availability of retinol for ATRA biosynthesis is determined by the uptake and retention of retinol in the cells. The uptake of retinol is believed to be mediated by “Stimulated by Retinoic Acid gene 6” (STRA6), a membrane receptor for plasma retinol binding protein 4 (RBP4) (reviewed in [8]), which delivers retinol to peripheral tissues from liver.

Lecithin:retinol acyltransferase (LRAT) converts retinol to its storage form, retinyl esters (reviewed in [9]), which can be hydrolyzed back to retinol by retinyl ester hydrolases when needed.

Thus far there is no evidence that retinyl ester hydrolases are regulated by vitamin A status, even though ATRA induces expression of both LRAT and STRA6 genes [10, 11].

It is well established that disruption of normal ATRA signaling is associated with numerous pathophysiological changes leading to carcinogenesis, impaired immune function, and metabolic dysregulation [12–16].

Skin is one of the major targets of ATRA signaling [17], where it is essential in the regulation of several aspects of skin cell proliferation, differentiation, apoptosis, and epidermal barrier function.

Alterations in retinoid metabolism, signaling and concentrations have been observed in various dermatoses, such as psoriasis [18], ichthyosis [19], and in atopic dermatitis [20]. Treatments with ATRA or synthetic RAR agonists appear to ameliorate some of these conditions.

For example, acitretin and tretinoin were shown to be effective for the treatment of actinic keratoses and to delay the development of SCCs in patients with xeroderma pigmentosum, a disease in which there is an inherited predisposition to ultraviolet-induced cancer [21, 22].

Systemic retinoids have also exhibited a chemoprophylactic effect in the treatment of non-melanoma skin cancer, particularly in organ transplant recipients and other high risk populations [23–25]. Unfortunately, because these agents must be continued indefinitely to maintain their protective benefits, the use of retinoids is limited due to their teratogenic potential and other intolerable adverse effects, including hypertriglyceridemia, mucocutaneous inflammation and hepatotoxicity.


RXR-alpha (Retinoid x receptor)

All About Retinoid X Receptors (RXR)
Sequence: MLGLNGVLKV PAHPSGNMAS FTKHICAICG DRSSGKHYGV YSCEGCKGFF KRTVRKDLTY TCRDNKDCLI DKRQRNRCQY CRYQKCLAMG MKREAVQEER QRGKDRNENE VESTSSANE Concentration: 1mg/ml The retinoid X receptor (RXR) is a pleiotropic nuclear receptor transcription factor that interacts with a variety of nuclear receptor dimeric partner. RXR binds cognate response elements as a homodimer in the presence of its ligand, 9-cis retinoic acid, or as a heterodimer with other members of the nuclear hormone receptor superfamily including retinoic acid receptors (RAR), thyroid hormone receptors (TR), vitamin D receptors and peroxisome proliferators-activated receptors (PPAR). The RXR family includes three difference isoforms ; RXR alpha, beta, gamma . Human RXR alpha gene is localized on 9q34.9 and encodes two major isoforms (RXR alpha1, RXR alpha2). The DNA binding domain of RXR (111-228aa) was over expressed in E.coli and purified by using conventional column chromatography techniques.

Function: Nuclear hormone receptor. Involved in the retinoic acid response pathway. Binds 9-cis retinoic acid (9C-RA). ARF6 acts as a key regulator of the tissue-specific adipocyte P2 (aP2) enhancer (By similarity).

Subunit: Homodimer or forms a heterodimer with peroxisome proliferator activated receptor gamma called adipocyte-specific transcription factor ARF6.

Interacts with NCOA3 and NCOA6 coactivators, leading to a strong increase of transcription of target genes. Interacts with FAM120B (By similarity). Interacts with SFPQ. Interacts with HCV core protein. Interacts with PELP1.

Interacts with SENP6. Interacts with DNTTIP2. Interacts with RNF8.

Subcellular Location: Nucleus.

Tissue Specificity: Highly expressed in liver, also found in lung, kidney and heart.

Domain: Composed of three domains: a modulating N-terminal domain, a DNA-binding domain and a C-terminal steroid-binding domain.

Ptm: Sumoylated on Lys-108; which negatively regulates transcriptional activity. Desumoylated specifically by SENP6.

Similarity: Belongs to the nuclear hormone receptor family. NR2 subfamily.

Similarity: Contains 1 nuclear receptor DNA-binding domain. 1. Si,J., Collins,S.J. (2002) Blood, 100(13);4401-4409

1. Zeng , M., et al (2002) J. Biol. Chem. 277(47) 45611-456181. Sharon Cresci, et. al. (1999) J. Biol. Chem. 274(36) 25668-256741. Li,G., et al. (2000) Biochem. Biophys. Res. Commun. 269(1) 54-57

1. Mangelsdorf, D. J., et al (1991) Cell 66(3) 555-561

Name Related Product Names Swissprot ID NCBI Acc Number Molecular Weight Purity Format Storage Datasheets/Manuals Intended Use
RXR-alpha (Retinoid x receptor) (GWB-D8BEA9)
RXR-alpha (Retinoid x receptor; 111-228aa, Human) Recombinant, expressed in E Coli; Retinoid X receptor alpha; Nuclear receptor subfamily 2 group B member 1 NR2B1RXR-alpha (Retinoid x receptor)RXRA
>= 95% by SDS PAGE
Liquid. In 20mM Tris-HCl pH7.5, 0.1M NaCl, 5mM ?-Mercaptoethanol
Store at -20C.
Printable datasheet for GWB-D8BEA9
Research Use Only



All About Retinoid X Receptors (RXR)

Retinoid X receptors (RXR) are members of the NR2B nuclear receptor family and are common binding partners to many other nuclear receptors, including PPARs, liver X receptors (LXRs) and vitamin D receptors (VDRs). There are three RXR subtypes; α, β and γ.

Retinoid X receptors (RXR) are members of the NR2B family of nuclear receptors and are common binding partners to many other nuclear receptors, including PPARs, liver X receptors (LXRs) and vitamin D receptors (VDR). RXR heterodimers act as ligand-dependent transcriptional regulators and increase the DNA-binding efficiency of its partner.

Despite numerous studies, the physiological role of RXRs have yet to been fully elucidated and, as they can also exist as homodimers, there is the possibility that an independent RXR signaling pathway exists.

There are three RXR subtypes; RXRα, RXRβ and RXRγ, each with two major isoforms (1 and 2). RXRα is expressed in the liver, kidney, epidermis and intestine, RXRβ is widely distributed and RXRγ is restricted to muscle, pituitary gland and certain parts of the brain.

External sources of pharmacological information for Retinoid X Receptors :

Tocris offers the following scientific literature for Retinoid X Receptors to showcase our products. We invite you to request* or download your copy today!

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A collection of over 750 products for cancer research, the guide includes research tools for the study of:

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Written by Alexander Moise, this review summarizes the nature of retinoid receptors, their isotype and isoform variants and modulation of retinoid signaling. Compounds available from Tocris are listed.

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Gene Species Gene Symbol Gene Accession No. Protein Accession No.
RXRα Human RXRA NM_002957 P19793
Mouse Rxra NM_011305 P28700
Rat Rxra NM_012805 Q05343
RXRβ Human RXRB NM_021976 P28702
Mouse Rxrb NM_011306 P28704
Rat Rxrb NM_206849 P49743
RXRγ Human RXRG NM_006917 P48443
Mouse Rxrg NM_011244 P18911
Rat Rxrg NM_031765 O70464


9-Cis-13,14-dihydroretinoic acid, a new endogenous mammalian ligand of retinoid X receptor and the active ligand of a potential new vitamin A category: vitamin A5

All About Retinoid X Receptors (RXR)

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The identity of the endogenous RXR ligand has not been conclusively determined, even though several compounds of natural origin, including retinoids and fatty acids, have been postulated to fulfill this role. Filling this gap, 9-cis-13,14-dihydroretinoic acid (9CDHRA) was identified as an endogenous RXR ligand in mice. This review examines the physiological relevance of various potential endogenous RXR ligands, especially 9CDHRA. The elusive steps in the metabolic synthesis of 9CDHRA, as well as the nutritional/nutrimetabolic origin of 9CDHRA, are also explored, along with the suitability of the ligand to be the representative member of a novel vitamin A class (vitamin A5).

Various studies have previously claimed the characterization of endogenous ligands of retinoid X receptor (RXR) as having the structure of either a retinoid or a fatty acid.1–5 Dawson and Xia6 summarized several studies on RXR ligands.

In all cases, however, the endogenous and nutrition-dependent levels required for RXR activation were virtually unknown, as they were either below the limit of detection or the amounts were too low for receptor activation.

3,7–9 The first endogenous, physiologically relevant RXR ligand, 9-cis-13,14-dihydroretinoic acid (9CDHRA), was recently characterized and found to induce moderate transcriptional RXR activation (≈ 10−6 to 10−7 M range).

10 This review will focus on the metabolic and nutrimetabolic pathways for the endogenous synthesis of 9CDHRA from related 13,14-dihydro retinoids, 9-cis retinoids, and 9-cis-13,14-dihydro retinoids and will examine potential nutritional precursors of 9CDHRA.

The metabolic pathway starting from these previously mentioned substances may support the notion that these substances represent a novel fully or partly independent pathway for vitamin A activity. It is proposed here that 9CDHRA may represent an end product of a novel vitamin A pathway for activation of the nuclear hormone receptors, the retinoic acid receptors (RARs), and, most importantly, the RXRs.

Known RXR ligands and their physiological relevance

Various derivatives, ranging from retinoids to fatty acids, have been proposed to function as endogenous ligands for RXR.

1–5 In particular, the potential endogenously occurring retinoid 9-cis retinoic acid was the subject of intense scrutiny by several research groups and became widely accepted as the endogenous RXR ligand.

11–16 Other groups with expertise in retinoid analysis, however, failed to detect 9-cis retinoic acid in humans and other mammals,7–10,14,17–21 thus calling into question the endogenous occurrence of this compound (Figure 1A7,10,14,17).

It seems that 9-cis retinoic acid may be found endogenously only after administration of high doses of synthetic retinoids or after intake of high amounts of foods that are rich in vitamin A derivatives retinol and retinyl esters, ie, amounts reached only in nutritional intervention studies.22,23

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(A) Chromatogram of retinoic acid isomers in mouse brain and mouse serum, obtained by high-performance liquid chromatography (HPLC)–UV (adapted from Rühl et al10,); (B) Internal probe of a 9CRA-coeluting peak found by Kane et al14,in mouse pancreas samples with chromatograms of chemical standards of 9CRA and ATRA in UV detection mode (right side) and tandem mass spectrometry (MS/MS) detection mode (left side with MS/MS settings of 301–205 m/z). Methodology: Pancreas samples from mice were obtained from Dr W. Krężel and were analyzed by the methods described previously,7 with modifications outlined by Rühl et al.10 In this setup, no additional prefilter was used before the HPLC column. This resulted in shorter retention times, as seen for ATRA when compared with Figure 1A; (C) 9-Cis isomerization pathway from ATRA to 9CRA, 13CRA and 9,13DCRA as well as from ATDHRA to 9CDHRA; (D) UV-induced isomerization of ATRA by electromagnetic radiation in the visible range (adapted from Kane et al17), with arrows marking individual isomers of retinoic acid.Abbreviations: ATDHRA, all-trans-13,14-dihydroretinoic acid; ATRA, all-trans retinoic acid; 9CDHRA, 9-cis-13,14-dihydroretinoic acid; 9CRA, 9-cis retinoic acid; hv, used here as a representative term indicating, in this reference, electromagnetic radiation; 13CRA, 13-cis retinoic acid; 9,13DCRA, 9,13-dicis retinoic acid.

There are several technical issues that may have led to some confusion in the detection of endogenous 9-cis retinoic acid. The first claim for the identification of 9-cis retinoic acid as an RXR ligand was made by Heyman et al1 and was the analysis of high-performance liquid chromatography (HPLC) profiles with UV detection using coelution alone as an indicator.

9-Cis retinoic acid was identified and claimed to be endogenously present. Unfortunately, this method of identification and detection was subsequently proven to be not entirely specific and not conclusive enough because various derivatives may also coelute with 9-cis retinoic acid.

7,10,14 More-conclusive evidence of the presence of a given compound than HPLC coelution would require the UV spectrum of the substance to be identified along with a complete mass spectrum or, better still, selective highly specific mass fragmentation patterns of the derivative to be identified.

7,10,24,25 Indeed, the identification of 9-cis retinoic acid by HPLC coelution alone should be considered as a tentative confirmation of low security, while strong evidence of the endogenous existence of 9-cis retinoic acid is still lacking (reviewed by de Lera et al26).

These studies into whether 9-cis retinoic acid is an endogenous derivative were performed more than 20 years ago, and developments in analytical techniques, especially HPLC coupled with mass spectrometry (MS), have improved significantly, particularly with regard to selectivity and sensitivity.

In recent years, 2 groups have established highly sensitive HPLC–MS methodologies for retinoid analysis in the low range of 0.01 to 0.001 ng/ml (or ng/g) for the quantification of various retinoids, including retinoic acid isomers such as 9-cis retinoic acid.

20,27 In one case a peak was identified using tandem mass spectrometry (MS/MS) under conditions that were specific for retinoic acids (301–205 m/z, using HPLC–MS/MS), and a peak detected in a pancreas sample, which coeluted with 9-cis retinoic acid, and endogenous concentration values were calculated to be in the range of 4 to 6 ng/g.

14 It was claimed that “these data validate 9CRA [9-cis retinoic acid] as a naturally occurring metabolite of vitamin A.”14 However, parallel UV detection of this peak was not performed, and it was argued in a subsequent review that the use of parallel UV detection is limited for physiological measurements.

12 This statement is unfortunately incorrect, and the use of UV detection, is indeed feasible, as demonstrated in various other studies.7,8,23,28,29 Concentrations of around 1 ng/ml (or ng/g), ie, lower than the claimed endogenous levels of 4 to 6 ng/g (0.1–0.2 nM) in pancreas,14 can easily be detected by UV measurements.

7,8,28 Confirmation of these results was attempted using our analytical methodology and mouse pancreas samples (Figure 1B). In this case, a peak was indeed detected in the MS/MS track (9.2 min retention time in MS/MS mode) and with a better separation in the UV track (9.3 min retention time in UV chromatogram).

However, this substance only coelutes closely to 9-cis retinoic acid (9.0 min retention time in MS/MS mode and 9.1 min in the UV chromatogram), and it is obvious, with this analytical setup, that this peak has a slightly longer retention time than the 9-cis retinoic acid standard (Figure 1B).

Our group is currently focused on the identification of this retinoid, and therefore additional data for peak identification, such as a UV spectrum to identify peaks, cannot be shown yet.

On the basis of the data reported by Kane et al,14 it is doubtful that 9-cis retinoic acid is an endogenously occurring retinoid in pancreas.

Once again, it should be noted that a simple coelution without additional structural elucidation is insufficient to claim definitively the existence of endogenous 9-cis retinoic acid.

The appearance of a peak with specific MS/MS characteristics coeluting with 9-cis retinoic acid has already been confirmed in a study by Rühl,7 and it was proven by parallel UV detection that this peak did not correspond to 9-cis retinoic acid.

In a second ultrasensitive retinoid analysis, the presence of potentially endogenous 9-cis retinoic acid was also determined using highly sensitive MS/MS detection.27 This identification of 9-cis retinoic acid was further proven by coelution with standards, and endogenous levels of 0.027 ng/ml (


Retinoid X Receptor- Proteins

All About Retinoid X Receptors (RXR)

 Creative BioMart Retinoid X Receptor Proteins Product List

 Retinoid X Receptor Proteins Background

Retinoid X receptors (RXR) belongs to the nuclear hormone receptor superfamily which includes steroid hormone, thyroid hormone, vitamin D receptors and nuclear receptors including retinoid X receptors, PPAR, LXR and PXR.

It is a unique protein in that it has the ability to form heterodimers with one third of the 48 other nuclear receptors giving it the potential to be involved and to converge a large array of signaling pathways.

The retinoid X receptors can be ligand dependent or independent and form three different types of dimers; RXR homodimers, permissive heterodimers, and non-permissive heterodimers.

When retinoid X receptor forms homodimers or permissive heterodimers (with PPAR, LXR, PXR etc.) it is amenable to retinoid X receptor ligand dependent activation.

This is due to the fact that the activation domain of the partner receptor is placed in proximity to retinoid X receptor helexis so that when RXR is activated by ligand, conformational changes cause direct stabilization of the activation domain of its partner. When RXR forms non-permissive heterodimers (with RAR, VDR, TR etc.

) it is not activated by ligand because binding of the other monomer to RXR allosterically inhibits it and the activation domain of the partner is not located in proximity to ligand activated residues in the retinoid X receptor interface.

An unusual protein-protein interaction property of retinoid X receptor is that it can exist in solution as a tetramer.

This is due to its unique dimerization interface that is stable in both a symmetric configuration (giving rise to homodimers) and asymmetric configuration (forming heterodimers).

When homodimers are formed, a new dimerization interface is formed that allows homodimer-homodimer association and thus the formation of tetramers. Since these tetramers form with high affinity, RXRs may be sequestered within the cell.

During development, RXR-α and β are ubiquitously expressed with the highest levels of RXR-α present in the liver, heart, intestines, kidney, spleen, placenta, and the epidermis. RXR-γ is expressed in all developing skeletal and cardiac muscles, the anterior pituitary, and the brain.

The expression of retinoid X receptors is tissue specific and often overlaps but occasionally retinoid X receptors are uniquely expressed. RXR-α is the primary isoform and supports the activity of all three retinoid X receptors.

Furthermore, RXR-α may be important in the expression of RXRγ since the RXRγ gene contains a Retinoid X Response Element.

Studies with mice lacking expression of RXR-α have found that these mice die in utero as a result of hypoplastic myocardium and RXR-α null mutations exhibit growth retardation, webbed digits  and defects in the chorioallantoic placenta. Loss of RXR-β and RXR-γ is not as severe since they can be compensated for by RXR-α which may explain why RXRγ-/- mouse mutants are viable and have no muscular defects even in compound mutant combinations.

The receptor dimers of retinoid X receptor and its partner, constituitively bind to specific DNA response elements in the promoters or enhancers of the genes they govern and DNA binding specificity is determined by the number of spacer nucleotides present between two direct repeats, everted repeats, or inverted repeats of the canonical binding sequence 5’-PuGGTCA. RXR/RAR heterodimers bind the Retinoic Acid Response Element (RARE) with a consensus half site separated by 2 or 5 nucleotides (DR2 or DR5) whereas RXR homodimers bind the Retinoid X Response Element (RXRE) which is separated by only one nucleotide (DR1). Selective response element recognition is due to a short sequence (the P box) located at the Cterminal base of the N-terminal C1 finger of the DNA Binding Domain (DBD) which interacts with the binding motif and to a weak dimerization function which encompases the N-terminal base of the CII finger (D-box) of the DBD. While RXR/RAR heterodimers bind more effectively to the RAREs than RXR homodimers, RXRs homodimers can bind RXREs with high affinity. RAREs can overlap with RXREs and since RXR/RAR heterodimers bind with a higher affinity than RXR homodimers, this may interfere with retinoid X receptor signaling.