Spatiotemporal retinoid-X receptor activation detected in live vertebrate embryos

Luria, A. R.; Furlow, J. David

doi:10.1073/pnas.0307053101

Cited by 26 publications

(17 citation statements)

References 67 publications

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“…The structures of the human unliganded RXRa (PDB code: 1LBD) 204 and the bound 9-cis RA (PDB code: 1FBY) 205 are shown spinal cord lit up, suggesting that endogenous ligand production took place. Using a similar system with green fluorescent protein as a reporter, Luria et al 72 have confirmed these results recently. They also obtained high RXR activation in the spinal cord, in the brain and in the olfactory epithelia.…”

Section: Ligandssupporting

confidence: 75%

Retinoid X receptors: X-ploring their (patho)physiological functions

Szántó

Narkar²,

Shen³

et al. 2004

Cell Death Differ

256

242

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Retinoid X receptor (RXR) belongs to a family of ligandactivated transcription factors that regulate many aspects of metazoan life. A class of nuclear receptors requires RXR as heterodimerization partner for their function. This places RXR in the crossroad of multiple distinct biological pathways. This and the fact that the debate on the endogenous ligand requirement for RXR is not yet settled make RXR still an enigmatic transcription factor. Here, we review some of the biology of RXR. We place RXR into the evolution of nuclear receptors, review structural details and ligands of the receptor. Then processes regulated by RXR are discussed focusing on the developmental roles deduced from studies on knockout animals and metabolic roles in diseases such as diabetes and atherosclerosis deduced from pharmacological studies. Finally, aspects of RXR's involvement in myeloid differentiation and apoptosis are summarized along with issues on RXR's suitability as a therapeutic target.

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Section: Ligandssupporting

confidence: 75%

Retinoid X receptors: X-ploring their (patho)physiological functions

Szántó

Narkar²,

Shen³

et al. 2004

Cell Death Differ

256

242

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“…Indeed, some have suggested that 9-cis-RA is not the endogenous ligand for RXR (28,29). However, Luria and Furlow (26) argued that 9-cis-RA was a ''logical candidate'' for the RXR ligand but that DHA could also be the important morphogen in Xenopus. Here, we show that DHA does not bind to locust RXR with such high affinity compared to 9-cis-RA and that 9-cis-RA is present, representing Ϸ55% of the retinoids in the locust embryo.…”

Section: Discussionmentioning

confidence: 99%

“…S1E), and indicated that RXR transcripts seen early in embryonic development (20) were translated and therefore of likely functional significance. In vertebrates, activated RXR (as opposed to heterodimerized RXR), is important for neurological promotion in embryos (25,26). Of the various forms of vertebrate RXRs, RXR␣ is thought to be of the greatest functional significance during mouse embryogenesis (27).…”

Section: Discussionmentioning

confidence: 99%

Locust retinoid X receptors: 9- Cis -retinoic acid in embryos from a primitive insect

Nowickyj¹,

Chithalen

Cameron

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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The retinoid X receptor (RXR) is activated by its often elusive cognate ligand, 9-cis-retinoic acid (9-cis-RA). In flies and moths, molting is mediated by a heterodimer ecdysone receptor consisting of the ecdysone monomer (EcR) and an RXR homolog, ultraspiracle (USP); the latter is believed to have diverged from its RXR origin. In the more primitive insect, Locusta migratoria (Lm), RXR is more similar to human RXRs than to USPs. LmRXR was detected in early embryos when EcR transcripts were absent, suggesting another role apart from ecdysone signaling. Recombinant LmRXRs bound 9-cis-RA and alltrans-RA with high affinity (IC 50 ‫؍‬ 61.2-107.7 nM; Kd ‫؍‬ 3 nM), similar to human RXR. To determine whether specific binding had functional significance, the presence of endogenous retinoids was assessed. Embryos were extracted by using modified Bligh and Dyer and solid-phase protocols to avoid the oily precipitate that makes this material unsuitable for assay. These extracts contained retinoids (5.4 nM) as assessed by RA-inducible Cyp26A1-promoter luciferase reporter cell lines. Furthermore, the use of HPLC and MS confirmed the presence of retinoids and identified in any embryo, 9-cis-RA, in addition to all-trans-RA. We estimate that whole embryos contain 3 nM RA, including 9-cis-RA at a concentration of 1.6 nM. These findings strongly argue for a functional role for retinoids in primitive insects and favor a model where signaling through the binding of 9-cis-RA to its RXR is established relatively early in evolution and embryonic development.all-trans-retinoic acid ͉ Locusta migratoria ͉ ultraspiracle I nsect development and metamorphosis are directed by two principal lipophilic hormones: 20-hydroxyecdysone (20-OH-Ec), the active molting hormone, and juvenile hormone (JH), whose titer determines the nature of the molt (1, 2). As demonstrated in the fruitfly, Drosophila melanogaster (Dm), 20-OH-Ec binds to the ecdysone receptor (EcR), which in turn is bound to its obligate heterodimerization partner ultraspiracle (USP), a homologue of the vertebrate retinoid X receptor (RXR) (3-6). As members of the nuclear receptor superfamily, EcR and USP/RXR share a common modular structure (7) comprised of a N-terminal variable domain (A/B), a DNA binding domain (C), hinge (D), and C-terminal ligand-binding domain (LBD; or domain E/F).The vertebrate RXRs are known heterodimeric partners of several members of the nuclear receptor superfamily, including the retinoid, thyroid, and vitamin D receptors (8). As demonstrated in vivo, these RXRs can also form homodimers and conceivably mediate an independent retinoid signaling pathway (9, 10). Indeed, the vertebrate RXRs are known ligand-activated transcription factors that bind 9-cis-retinoic acid (9-cis-RA), a stereoisomer of the vitamin A derivative, all-trans-RA (11, 12). RA receptors (RARs), reported only in vertebrates, are distinct in that they bind both all-trans-RA and 9-cis-RA with high affinity (13, 6). In contrast to the vertebrate RXRs, crystal structures reveal that DmUSP and t...

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“…During organ morphogenesis, the retinoic acid receptor (RAR) and RXR are both expressed in neural and digestive tissues (Luria and Furlow, 2004). These receptors heterodimerize to affect RA signaling, supporting a role for RA signaling in morphogenesis of these specific tissues.…”

Section: Introductionmentioning

confidence: 99%

Acute atrazine exposure disrupts matrix metalloproteinases and retinoid signaling during organ morphogenesis in Xenopus laevis

Lenkowski

McLaughlin

2010

J of Applied Toxicology

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Exposure to the herbicide atrazine disrupts many developmental processes in non-target animals. Atrazine exposure during organ morphogenesis in amphibians results in dramatic malformations; the mechanism by which this happens has not been described. We have taken a candidate gene approach to explore two possible mechanisms by which acute atrazine exposure causes extensive malformations in several tissues in Xenopus laevis tadpoles. Using a static renewal system, we exposed tadpoles to atrazine for 6-48 h during organ morphogenesis (Nieuwkoop and Faber stage 42). We observed degradation of cranial cartilage and differentiated muscle in the head, gut and somites of exposed tadpoles. Additionally, transcript levels of matrix metalloproteinases (MMPs), specifically both MMP9TH and MMP18, increased in atrazine-exposed tadpoles in a dose-response test, and MMP18 increased as early as 6 h after exposure began. Gelatinase MMP activity was also altered by atrazine exposure, indicating that atrazine disrupts gene function at the level of transcription and protein activity. Furthermore, transcript levels of the enzyme Xcyp26, an enzyme in the retinoic acid signaling pathway, significantly decreased in the intestines of tadpoles exposed to 10 or 35 mg l(-1) atrazine for 48 h. Our results suggest two mechanisms by which atrazine can disrupt tissue morphogenesis: through misregulation of MMPs that are critical in extracellular matrix remodeling throughout development and the disruption of retinoic acid signaling. This study begins to describe conserved vertebrate developmental processes that are disrupted by atrazine exposure.

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Spatiotemporal retinoid-X receptor activation detected in live vertebrate embryos

Cited by 26 publications

References 67 publications

Retinoid X receptors: X-ploring their (patho)physiological functions

Retinoid X receptors: X-ploring their (patho)physiological functions

Locust retinoid X receptors: 9- Cis -retinoic acid in embryos from a primitive insect

Acute atrazine exposure disrupts matrix metalloproteinases and retinoid signaling during organ morphogenesis in Xenopus laevis

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