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Pierre Chambon - One of the best experts on this subject based on the ideXlab platform.

  • a microenvironment induced myeloproliferative syndrome caused by Retinoic Acid Receptor γ deficiency
    Cell, 2007
    Co-Authors: Carl R Walkley, Pierre Chambon, Gemma Haines Olsen, Sebastian Dworkin, Stewart A Fabb, Jeremy Swann, Grant A Mcarthur, Susan V Westmoreland, David T Scadden
    Abstract:

    Myeloproliferative syndromes (MPS) are a heterogeneous subclass of nonlymphoid hematopoietic neoplasms which are considered to be intrinsic to hematopoietic cells. The causes of MPS are largely unknown. Here, we demonstrate that mice deficient for Retinoic Acid Receptor gamma (RARgamma), develop MPS induced solely by the RARgamma-deficient microenvironment. RARgamma(-/-) mice had significantly increased granulocyte/macrophage progenitors and granulocytes in bone marrow (BM), peripheral blood, and spleen. The MPS phenotype continued for the lifespan of the mice and was more pronounced in older mice. Unexpectedly, transplant studies revealed this disease was not intrinsic to the hematopoietic cells. BM from wild-type mice transplanted into mice with an RARgamma(-/-) microenvironment rapidly developed the MPS, which was partially caused by significantly elevated TNFalpha in RARgamma(-/-) mice. These data show that loss of RARgamma results in a nonhematopoietic cell-intrinsic MPS, revealing the capability of the microenvironment to be the sole cause of hematopoietic disorders.

  • Retinoic Acid Receptor α regulates pulmonary alveolus formation in mice after but not during perinatal period
    American Journal of Physiology-lung Cellular and Molecular Physiology, 2003
    Co-Authors: Gloria Decarlo Massaro, Donald Massaro, Pierre Chambon
    Abstract:

    The formation of pulmonary alveoli in mice and rats by subdivision of alveolar saccules that constitute the newborn's gas-exchange region ends by approximately postnatal day 14. However, alveoli continue to form after age 14 days until age approximately 40 days by means other than septation of the saccules present at birth. With the use of morphometric procedures and Retinoic Acid Receptor (RAR)-alpha+/+ and RAR-alpha-/- mice, we now show the volume of individual alveoli (va), the number of alveoli (Na), and alveolar surface area (Sa) are the same in 14-day-old RAR-alpha+/+ and RAR-alpha-/- mice. However, at age 50 days, va is larger, and Na and Sa are smaller, in RAR-alpha-/- than in RAR-alpha+/+ mice, although total lung volume is the same in both groups. These findings, and prior data showing RAR-beta is an endogenous inhibitor of alveolus formation during, but not after, the perinatal period, indicate there are developmental period-specific regulators of alveolus formation and that total lung volume and alveolar dimensions may have different regulators.

  • Retinoic Acid Receptor β an endogenous inhibitor of the perinatal formation of pulmonary alveoli
    Physiological Genomics, 2000
    Co-Authors: Gloria Decarlo Massaro, Waiyee Chan, Norbert B Ghyselinck, Donald Massaro, Linda Biadasz Clerch, Pierre Chambon, Roshantha A S Chandraratna
    Abstract:

    Pulmonary alveoli are formed, in part, by subdivision (septation) of the gas-exchange saccules of the immature lung. Septation is developmentally regulated, and failure to septate at the appropriate time is not followed by delayed spontaneous septation. We report Retinoic Acid Receptor (RAR) β knockout mice exhibit premature septation; in addition, they form alveoli twice as fast as wild-type mice during the period of septation but at the same rate as wild-type mice thereafter. Consistent with the perinatal effect of RARβ knockout, RARβ agonist treatment of newborn rats impairs septation. These results 1 ) identify RARβ as the first recognized endogenous signaling that inhibits septation, 2 ) demonstrate premature onset of septation may be induced, and 3 ) show the molecular signaling regulating alveolus formation differs during and after the period of septation. Suppressing perinatal RARβ signaling by RARβ antagonists may offer a novel, nonsurgical, means of preventing, or remediating, failed septation in prematurely born children.

  • tissue specific expression of Retinoic Acid Receptor isoform transcripts in the mouse embryo
    Mechanisms of Development, 2000
    Co-Authors: Richard Mollard, Pierre Chambon, Stephane Viville, Simon J Ward, Didier Decimo, Pascal Dolle
    Abstract:

    The three murine Retinoic Acid Receptor (RAR) genes each contain two distinct promoters which give rise to protein isoforms differing in their N-terminal regions. This study used in situ hybridization to describe the expression patterns of RARalpha1, RARalpha2, RARbeta1/3, RARbeta2/4, RARgamma1 and RARgamma2 isoform transcripts during mouse embryogenesis. RARalpha1 transcripts are widely distributed, with the exception of the central nervous system. Highest expression is found in developing muscle, pituitary gland and various epithelia. On the other hand, RARalpha2 is essentially expressed along the spinal cord up to the hindbrain 7th rhombomere and in the 4th rhombomere, pons and developing basal ganglia (corpus striatum and pallidum). RARbeta2/4 transcripts account for most of the previously described RARbeta expression features being expressed specifically, or more prominently than RARbeta1/3, in foregut endoderm and its derivatives, olfactory and periocular mesenchyme, urogenital region, proximal limb bud mesenchyme and later within interdigital regions. RARbeta1/3 is more prominently expressed in the developing heart outflow tract mesenchyme, intervertebral disks, midgut loop mesenchyme and umbilical vessel walls. RARbeta1/3 and RARbeta2/4 are coexpressed in the developing corpus striatum. They exhibit, however, distinct dorsoventral distributions along the spinal cord and caudal hindbrain. RARgamma2 is the RARgamma isoform expressed at high levels in the caudal neural groove at embryonic day 8.5. At later stages, both RARgamma isoforms are essentially coexpressed, although the progressive restriction of RARgamma1 transcripts to craniofacial or limb precartilaginous condensations appears to precede that of RARgamma2.

  • regulation of dopaminergic pathways by retinoids activation of the d2 Receptor promoter by members of the Retinoic Acid Receptor retinoid x Receptor family
    Proceedings of the National Academy of Sciences of the United States of America, 1997
    Co-Authors: Tarek A Samad, Pierre Chambon, Wojciech Krezel, Emiliana Borrelli
    Abstract:

    Dopamine is a neuromodulator involved in the control of key physiological functions. Dopamine-dependent signal transduction is activated through the interaction with membrane Receptors of the seven-transmembrane domain G protein-coupled family. Among them, dopamine D2 Receptor is highly expressed in the striatum and the pituitary gland as well as by mesencephalic dopaminergic neurons. Lack of D2 Receptors in mice leads to a locomotor parkinsonian-like phenotype and to pituitary tumors. The D2 Receptor promoter has characteristics of a housekeeping gene. However, the restricted expression of this gene to particular neurons and cells points to a strict regulation of its expression by cell-specific transcription factors. We demonstrate here that the D2 Receptor promoter contains a functional Retinoic Acid response element. Furthermore, analysis of Retinoic Acid Receptor-null mice supports our finding and shows that in these animals D2 Receptor expression is reduced. This finding assigns to retinoids an important role in the control of gene expression in the central nervous system.

Saverio Minucci - One of the best experts on this subject based on the ideXlab platform.

  • recruitment of the histone methyltransferase suv39h1 and its role in the oncogenic properties of the leukemia associated pml Retinoic Acid Receptor fusion protein
    Molecular and Cellular Biology, 2006
    Co-Authors: Roberta Carbone, Saverio Minucci, Oronza A Botrugno, Simona Ronzoni, Alessandra Insinga, Luciano Di Croce, Pier Giuseppe Pelicci
    Abstract:

    Leukemia-associated fusion proteins establish aberrant transcriptional programs, which result in the block of hematopoietic differentiation, a prominent feature of the leukemic phenotype. The dissection of the mechanisms of deregulated transcription by leukemia fusion proteins is therefore critical for the design of tailored antileukemic strategies, aimed at reestablishing the differentiation program of leukemic cells. The acute promyelocytic leukemia (APL)-associated fusion protein PML-Retinoic Acid Receptor (RAR) behaves as an aberrant transcriptional repressor, due to its ability to induce chromatin modifications (histone deacetylation and DNA methylation) and silencing of PML-RAR target genes. Here, we indicate that the ultimate result of PML-RAR action is to impose a heterochromatin-like structure on its target genes, thereby establishing a permanent transcriptional silencing. This effect is mediated by the previously described association of PML-RAR with chromatin-modifying enzymes (histone deacetylases and DNA methyltransferases) and by recruitment of the histone methyltransferase SUV39H1, responsible for trimethylation of lysine 9 of histone H3.

  • retinoid x Receptor rxr within the rxr Retinoic Acid Receptor heterodimer binds its ligand and enhances retinoid dependent gene expression
    Molecular and Cellular Biology, 1997
    Co-Authors: Saverio Minucci, Mark Leid, Reiko Toyama, Jean Pierre Saintjeannet, Valerie J Peterson, Valerie J Horn, Jane E Ishmael, Nisan Bhattacharyya, Anup Dey, Igor B Dawid
    Abstract:

    Retinoic Acid Receptor (RAR) and retinoid X Receptor (RXR) form heterodimers and regulate retinoid-mediated gene expression. We studied binding of RXR- and RAR-selective ligands to the RXR-RAR heterodimer and subsequent transcription. In limited proteolysis analyses, both RXR and RAR in the heterodimer bound their respective ligands and underwent a conformational change in the presence of a Retinoic Acid-responsive element. In reporter analyses, the RAR ligand (but not the RXR ligand), when added singly, activated transcription, but coaddition of the two ligands led to synergistic activation of transcription. This activation required the AF-2 domain of both RXR and RAR. Genomic footprinting analysis was performed with P19 embryonal carcinoma cells, in which transcription of the RARbeta gene is induced upon retinoid addition. Paralleling the reporter activation data, only the RAR ligand induced in vivo occupancy of the RARbeta2 promoter when added singly. However, at suboptimal concentrations of RAR ligand, coaddition of the RXR ligand increased the stability of promoter occupancy. Thus, liganded RXR and RAR both participate in transcription. Finally, when these ligands were tested for teratogenic effects on zebra fish and Xenopus embryos, we found that coadministration of the RXR and RAR ligands caused more severe abnormalities in these embryos than either ligand alone, providing biological support for the synergistic action of the two ligands.

Jun Dai - One of the best experts on this subject based on the ideXlab platform.

  • Retinoic Acid Receptor related orphan Receptor rorα regulates differentiation and survival of keratinocytes during hypoxia
    Journal of Cellular Physiology, 2018
    Co-Authors: Longjian Zhou, Jun Dai
    Abstract:

    Low O2 pressures present in the microenvironment of epidermis control keratinocyte differentiation and epidermal barrier function through hypoxia inducible factors (HIFs) dependent gene expression. This study focuses on investigating relations of the Retinoic Acid Receptor-related orphan Receptor alpha (RORα) to HIF-1α in keratinocytes under hypoxic conditions. The expression level of RORα is significantly elevated under hypoxia in both human and murine keratinocytes. Gene silencing of RORA attenuates hypoxia-stimulated expression of genes related to late differentiation and epidermal barrier function, and leads to an enhanced apoptotic response. While the hypoxic induction of RORα is dependent on HIF-1α, RORα is in turn critical for nuclear accumulation of HIF-1α and activation of HIF transcriptional activity. These results collectively suggest that RORα functions as an important mediator of HIF-1α activities in regulating keratinocyte differentiation/survival and epidermal barrier function during the oxygen sensing stage.

Shanthini Sockanathan - One of the best experts on this subject based on the ideXlab platform.

  • epithelial Retinoic Acid Receptor β regulates serum amyloid a expression and vitamin a dependent intestinal immunity
    Proceedings of the National Academy of Sciences of the United States of America, 2019
    Co-Authors: Sureka Gattu, Ye Ji Bang, Kelly A Ruhn, Mihir Pendse, Chaitanya Dende, Andrew L Chara, Tamia A Harris, Yuhao Wang, Zheng Kuang, Shanthini Sockanathan
    Abstract:

    Vitamin A is a dietary component that is essential for the development of intestinal immunity. Vitamin A is absorbed and converted to its bioactive derivatives retinol and Retinoic Acid by the intestinal epithelium, yet little is known about how epithelial cells regulate vitamin A-dependent intestinal immunity. Here we show that epithelial cell expression of the transcription factor Retinoic Acid Receptor β (RARβ) is essential for vitamin A-dependent intestinal immunity. Epithelial RARβ activated vitamin A-dependent expression of serum amyloid A (SAA) proteins by binding directly to Saa promoters. In accordance with the known role of SAAs in regulating Th17 cell effector function, epithelial RARβ promoted IL-17 production by intestinal Th17 cells. More broadly, epithelial RARβ was required for the development of key vitamin A-dependent adaptive immune responses, including CD4+ T-cell homing to the intestine and the development of IgA-producing intestinal B cells. Our findings provide insight into how the intestinal epithelium senses dietary vitamin A status to regulate adaptive immunity, and highlight the role of epithelial cells in regulating intestinal immunity in response to diet.

  • epithelial Retinoic Acid Receptor β regulates serum amyloid a expression and vitamin a dependent intestinal immunity
    bioRxiv, 2019
    Co-Authors: Sureka Gattu, Ye Ji Bang, Kelly A Ruhn, Mihir Pendse, Chaitanya Dende, Andrew L Chara, Tamia A Harris, Yuhao Wang, Zheng Kuang, Shanthini Sockanathan
    Abstract:

    Abstract Vitamin A is a dietary component that is essential for the development of intestinal immunity. Vitamin A is absorbed and converted to its bioactive derivatives retinol and Retinoic Acid by the intestinal epithelium, yet little is known about how epithelial cells regulate vitamin A-dependent intestinal immunity. Here we show that epithelial cell expression of the transcription factor Retinoic Acid Receptor β (RARβ) is essential for vitamin A-dependent intestinal immunity. Epithelial RARβ activated vitamin A-dependent expression of serum amyloid A (SAA) proteins by binding directly to Saa promoters. In accordance with the known role of SAAs in regulating Th17 cell effector function, epithelial RARβ promoted IL-17 production by intestinal Th17 cells. More broadly, epithelial RARβ was required for the development of key vitamin A-dependent adaptive immune responses, including CD4+ T cell homing to the intestine and the development of immunoglobulin A-producing intestinal B cells. Our findings provide insight into how the intestinal epithelium senses dietary vitamin A status to regulate adaptive immunity and highlight the role of epithelial cells in regulating intestinal immunity in response to diet. Significance Statement Vitamin A is a nutrient that is essential for the development of intestinal immunity. It is absorbed by gut epithelial cells which convert it to retinol and Retinoic Acid. Here we show that the transcription factor Retinoic Acid Receptor β (RARβ) allows epithelial cells to sense vitamin A in the diet and regulate vitamin A-dependent immunity in the intestine. We find that epithelial RARβ regulates several intestinal immune responses, including production of the immunomodulatory protein serum amyloid A, T cell homing to the intestine, and B cell production of immunoglobulin A. Our findings provide new insight into how epithelial cells sense vitamin A to regulate intestinal immunity and highlight why vitamin A is so important for immunity to infection.

Yongjun Wang - One of the best experts on this subject based on the ideXlab platform.

  • regulation of expression of citrate synthase by the Retinoic Acid Receptor related orphan Receptor α rorα
    PLOS ONE, 2012
    Co-Authors: Christine Crumbley, Yongjun Wang, Subhashis Banerjee, Thomas P Burris
    Abstract:

    The Retinoic Acid Receptor-related orphan Receptor α (RORα) is a member of the nuclear Receptor superfamily of transcription factors that plays an important role in regulation of the circadian rhythm and metabolism. Mice lacking a functional RORα display a range of metabolic abnormalities including decreased serum cholesterol and plasma triglycerides. Citrate synthase (CS) is a key enzyme of the citric Acid cycle that provides energy for cellular function. Additionally, CS plays a critical role in providing citrate derived acetyl-CoA for lipogenesis and cholesterologenesis. Here, we identified a functional RORα response element (RORE) in the promoter of the CS gene. ChIP analysis demonstrates RORα occupancy of the CS promoter and a putative RORE binds to RORα effectively in an electrophoretic mobility shift assay and confers RORα responsiveness to a reporter gene in a cotransfection assay. We also observed a decrease in CS gene expression and CS enzymatic activity in the staggerer mouse, which has a mutation of in the Rora gene resulting in nonfunctional RORα protein. Furthermore, we found that SR1001 a RORα inverse agonist eliminated the circadian pattern of expression of CS mRNA in mice. These data suggest that CS is a direct RORα target gene and one mechanism by which RORα regulates lipid metabolism is via regulation of CS expression.

  • regulation of fgf21 expression and secretion by Retinoic Acid Receptor related orphan Receptor α
    Journal of Biological Chemistry, 2010
    Co-Authors: Yongjun Wang, Laura A Solt, Thomas P Burris
    Abstract:

    Fibroblast growth factor 21 (FGF21) is a hormone produced by fat and the liver that plays an important role in lipid metabolism. FGF21 expression is induced by peroxisome proliferator-actived Receptor α in response to physiological conditions requiring increased fatty Acid oxidation. Retinoic Acid Receptor-related Receptor α (RORα) is another nuclear Receptor that plays a critical role in lipid metabolism as well as in regulation of the circadian rhythm. In this study we demonstrate that RORα directly regulates the expression and secretion of FGF21. A canonical ROR response element was identified in the proximal promoter of the FGF21 gene and shown to exhibit functional activity. Overexpression of RORα in HepG2 cells resulted in increased expression and secretion of FGF21. Suppression of RORα expression caused a decrease in FGF21 expression and secretion, suggesting that RORα contributes to the basal expression of FGF21. These data suggest that one mechanism by which RORα regulates lipid metabolism may be by modulation of FGF21 secretion. Furthermore, this study identifies a clear link between RORα, a key regulator of the mammalian clock, and FGF21, an important hormone regulating glucose and lipid homeostasis.

  • modulation of Retinoic Acid Receptor related orphan Receptor α and γ activity by 7 oxygenated sterol ligands
    Journal of Biological Chemistry, 2010
    Co-Authors: Yongjun Wang, Christine Crumbley, Laura A Solt, Naresh Kumar, Timothy I Richardson, Leah M Helvering, Ruben D Garciaordonez, Keith R Stayrook, Xi Zhang, Scott J Novick
    Abstract:

    Abstract The Retinoic Acid Receptor-related orphan Receptors α and γ (RORα (NR1F1) and RORγ (NR1F3)) are orphan nuclear Receptors and perform critical roles in regulation of development, metabolism, and immune function. Cholesterol and cholesterol sulfate have been suggested to be RORα ligands, but the physiological significance is unclear. To date, no endogenous RORγ ligands have been described. Here, we demonstrate that 7-oxygenated sterols function as high affinity ligands for both RORα and RORγ by directly binding to their ligand-binding domains (Ki ∼20 nm), modulating coactivator binding, and suppressing the transcriptional activity of the Receptors. One of the 7-oxygenated sterols, 7α-hydroxycholesterol (7α-OHC), serves as a key intermediate in bile Acid metabolism, and we show that 7α-OHC modulates the expression of ROR target genes, including Glc-6-Pase and phosphoenolpyruvate carboxykinase, in an ROR-dependent manner. Furthermore, glucose output from hepatocytes is suppressed by 7α-OHC functioning as an RORα/γ ligand. Thus, RORα and RORγ are ligand-regulated members of the NR superfamily and may serve as sensors for 7-oxygenated sterols.