An understanding of the differences and similarities of the retinoid X receptor (RXR) and retinoic acid receptor (RAR) systems requires knowledge of the diversity of their family members, their patterns of expression, and their pharmacological response to ligands. In this paper we report the isolation of a family of mouse RXR genes encoding three distinct receptors (RXR alpha, beta, and gamma). They are closely related to each other in their DNA- and ligand-binding domains but are quite divergent from the RAR subfamily in both structure and ligand specificity. Recently, we demonstrated that all-trans retinoic acid (RA) serves as a "pro-hormone" to the isomer 9-cis RA, which is a high-affinity ligand for the human RXR alpha. We extend those findings to show that 9-cis RA is also "retinoid X" for mouse RXR alpha, beta, and gamma. Trans-activation analyses show that although all three RXRs respond to a variety of endogenous retinoids, 9-cis RA is their most potent ligand and is up to 40-fold more active than all-trans RA. Northern blot and in situ hybridization analyses define a broad spectrum of expression for the RXRs, which display unique patterns and only partially overlap themselves and the RARs. This study suggests that the RXR family plays critical roles in diverse aspects of development, from embryo implantation to organogenesis and central nervous system differentiation, as well as in adult physiology.
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"Retinoic acid receptors were cloned in the late 1980s and early 1990s by several laboratories; these include all-trans retinoic acid receptors (RARs) (Benbrook et al., 1988; Brand et al., 1988; Pet Kovitch et al., 1987; Ragsdale et al., 1989) and 9-cis retinoic acid receptors (RXRs) (Fleishhauer et al., 1990; Hamada et al., 1989; Leid et al., 1992; Li et al., 2000; Liu and Linney, 1993; Mangelsdorf et al., 1990, 1992), identifying a new class of nuclear receptors (NRs) being activated by nutrients or their derivatives and therefore distinguishable from the previously characterized steroid hormone receptors (SRs) that are regulated by endocrine cues. Both types of receptors (steroid and nuclear receptors) are part of a large family of transcription factors sharing structural and functional properties, a majority of them being regulated by a hydrophobic ligand. "
"RXR is an unusual and somewhat neglected member of the nuclear receptor superfamily because it is still not known how this receptor interacts with the genome and regulates gene expression upon ligand activation. It is expressed in every cell type and is required for postnatal life in mice (Mangelsdorf et al. 1992; for review, see Szanto et al. 2004). Its presumed main molecular function is to regulate the activity of a dozen or so nuclear receptors. "
[Show abstract][Hide abstract] ABSTRACT: RXR signaling is predicted to have a major impact in macrophages, but neither the biological consequence nor the genomic basis of its ligand activation is known. Comprehensive genome-wide studies were carried out to map liganded RXR-mediated transcriptional changes, active binding sites, and cistromic interactions in the context of the macrophage genome architecture. The macrophage RXR cistrome has 5200 genomic binding sites, which are not impacted by ligand. Active enhancers are characterized by PU.1 binding, an increase of enhancer RNA, and P300 recruitment. Using these features, 387 liganded RXR-bound enhancers were linked to 226 genes, which predominantly reside in CTCF/cohesin-limited functional domains. These findings were molecularly validated using chromosome conformation capture (3C) and 3C combined with sequencing (3C-seq), and we show that selected long-range enhancers communicate with promoters via stable or RXR-induced loops and that some of the enhancers interact with each other, forming an interchromosomal network. A set of angiogenic genes, including Vegfa, has liganded RXR-controlled enhancers and provides the macrophage with a novel inducible program.
Genes & development 07/2014; 28(14):1562-77. DOI:10.1101/gad.242685.114 · 10.80 Impact Factor
"The TR can operate as a homodimer to drive gene expression but it is also frequently heterodimerized with the retinoid X receptor (RXR) . The ligand-binding domain (LBD) of TR primarily binds to T3, the most active form of TH, whereas the RXR LBD binds 9-cis-retinoic acid (9cRA) –. In the TR/RXR heterodimer, RXR was once considered to be non-permissive; i.e., 9cRA was not able to transactivate target gene expression . "
[Show abstract][Hide abstract] ABSTRACT: Thyroid hormone (TH) exerts its effects by binding to the thyroid hormone receptor (TR), which binds to TH response elements (TREs) to regulate target gene expression. We investigated the relative ability of liganded homodimers TR and retinoid X receptor (RXR), and the heterodimer TR/RXR, to regulate gene expression for the TRE half-site organizations: direct repeat 4 (DR4), inverted repeat 0 (IR0) and everted repeat 6 (ER6). Luciferase reporter assays using a DR4 TRE suggest that both the TR homodimer and TR/RXR heterodimer regulate luciferase expression in the presence of their respective ligands. However, in the presence of the IR0 TRE, transfection with TR/RXR and RXR alone increased luciferase activity and there was no effect of TR alone. The presence of 9-cis-retinoic acid was necessary for luciferase expression, whereas TH treatment alone was insufficient. For the ER6 TRE, transfection with TR/RXR, TR alone and RXR alone (in the presence of their respective ligands) all caused a significant increase in luciferase activity. When both ligands were present, transfection with both TR/RXR caused more activation. Finally, we investigated the efficacy of the TR-antagonist 1-850 in inhibiting transcription by TR or TR/RXR at DR4 and ER6 TREs. We found that 1-850 did not suppress luciferase activation in the presence of TR/RXR for the ER6 TRE, suggesting conformational changes of the ligand binding domain of the TR when bound to different TRE half-site organizations. Collectively, the findings indicate that there are fundamental differences between TRE configurations that affect nuclear receptor interactions with the response element and ability to bind ligands and antagonists.
PLoS ONE 06/2014; 9(6):e101155. DOI:10.1371/journal.pone.0101155 · 3.23 Impact Factor