scholarly journals Active repression by unliganded retinoid receptors in development

2003 ◽  
Vol 161 (2) ◽  
pp. 223-228 ◽  
Author(s):  
Andrea D. Weston ◽  
Bruce Blumberg ◽  
T. Michael Underhill
Keyword(s):  
Retinoic Acid ◽  
Cell Fate ◽  
Thyroid Hormone Receptor ◽  
Trichostatin A ◽  
Skeletal Development ◽  
Dominant Negative ◽  
Retinoid Receptors ◽  
Head Formation ◽  
Developmental Role

The retinoid receptors have major roles throughout development, even in the absence of ligand. Here, we summarize an emerging theme whereby gene repression, mediated by unliganded retinoid receptors, can dictate cell fate. In addition to activating transcription, retinoid receptors actively repress gene transcription by recruiting cofactors that promote chromatin compaction. Two developmental processes for which gene silencing by the retinoid receptors is essential are head formation in Xenopus and skeletal development in the mouse. Inappropriate repression, by oncogenic retinoic acid (RA)**Abbreviations used in this paper: APL, acute promyelocytic leukemia; dnRARα, dominant–negative version of the RARα; E, embryonic age; HDAC, histone deacetylase; LCoR, ligand-dependent corepressor; NCoR, nuclear receptor corepressor; RA, retinoic acid; RAR, RA receptor; RARE, RXR homodimer bound to bipartite response element; RXR, retinoid X receptor; TSA, trichostatin A; CYP26, cytochrome p450, 26; TR, thyroid hormone receptor. receptor (RAR) fusion proteins, blocks myeloid differentiation leading to a rare form of leukemia. Our current understanding of the developmental role of retinoid repression and future perspectives in this field are discussed.

Suppression of GATA factor activity causes axis duplication in Xenopus

Development ◽  
1998 ◽  
Vol 125 (23) ◽  
pp. 4595-4605 ◽  
Author(s):  
T.G. Sykes ◽  
A.R. Rodaway ◽  
M.E. Walmsley ◽  
R.K. Patient
Keyword(s):  
Cell Fate ◽  
Homeobox Gene ◽  
Dominant Negative ◽  
Gata Factor ◽  
Dorsoventral Axis ◽  
Morphogenetic Protein ◽  
Head Formation ◽  
Bmp Signalling ◽  
Bmp Antagonist

In Xenopus, the dorsoventral axis is patterned by the interplay between active signalling in ventral territories, and secreted antagonists from Spemann's organiser. Two signals are important in ventral cells, bone morphogenetic protein-4 (BMP-4) and Wnt-8. BMP-4 plays a conserved role in patterning the vertebrate dorsoventral axis, whilst the precise role of Wnt-8 and its relationship with BMP-4, are still unclear. Here we have investigated the role played by the GATA family of transcription factors, which are expressed in ventral mesendoderm during gastrulation and are required for the differentiation of blood and endodermal tissues. Injection ventrally of a dominant-interfering GATA factor (called G2en) induced the formation of secondary axes that phenocopy those induced by the dominant-negative BMP receptor. However, unlike inhibiting BMP signalling, inhibiting GATA activity in the ectoderm does not lead to neuralisation. In addition, analysis of gene expression in G2en injected embryos reveals that at least one known target gene for BMP-4, the homeobox gene Vent-2, is unaffected. In contrast, the expression of Wnt-8 and the homeobox gene Vent-1 is suppressed by G2en, whilst the organiser-secreted BMP antagonist chordin becomes ectopically expressed. These data therefore suggest that GATA activity is essential for ventral cell fate and that subsets of ventralising and dorsalising genes require GATA activity for their expression and suppression, respectively. Finally, using G2en, we show that suppression of Wnt-8 expression, in conjunction with blocked BMP signalling, does not lead to head formation, suggesting that the head-suppressing Wnt signal may not be Wnt-8.

Developmental role of endogenous retinoids in the determination of morphallactic field in budding tunicates

Development ◽  
1993 ◽  
Vol 117 (3) ◽  
pp. 835-845 ◽  
Author(s):  
K. Kawamura ◽  
K. Hara ◽  
S. Fujiwara
Keyword(s):  
Retinoic Acid ◽  
Aldehyde Dehydrogenase ◽  
Ectopic Expression ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
Proximal Extremity ◽  
Developmental Role

We have extracted retinoids from the budding tunicate Polyandrocarpa misakiensis and, using HPLC, identified some major peaks as cis-retinal, all-trans-retinal and all-trans-retinoic acid, of which cis-retinal was most abundant (~2 micromolar). In developing buds, the amount of cis-retinal was about one-fifth that of the adult animals. In those buds, aldehyde dehydrogenase, which could metabolize retinal in vitro, was expressed in epithelial cells and then in mesenchymal cells at the proximal extremity, that is, the future developmental field of the bud. Exogenous retinoic acid comparable to the endogenous level could induce an additional field at the distal end of the bud, resulting in a double monster. The induction always accompanied an ectopic expression of aldehyde dehydrogenase. The results of this work suggest that retinoic acid or related molecule(s) act as an endogenous trigger of morphallactic development of Polyandrocarpa buds.

scholarly journals In vivo analysis of the role of aberrant histone deacetylase recruitment and RARα blockade in the pathogenesis of acute promyelocytic leukemia

2006 ◽  
Vol 203 (4) ◽  
pp. 821-828 ◽  
Author(s):  
Hiromichi Matsushita ◽  
Pier Paolo Scaglioni ◽  
Mantu Bhaumik ◽  
Eduardo M. Rego ◽  
Lu Fan Cai ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Fusion Protein ◽  
Acute Promyelocytic Leukemia ◽  
Histone Deacetylases ◽  
Retinoic Acid Receptor ◽  
Promyelocytic Leukemia ◽  
Dominant Negative

The promyelocytic leukemia–retinoic acid receptor α (PML-RARα) protein of acute promyelocytic leukemia (APL) is oncogenic in vivo. It has been hypothesized that the ability of PML-RARα to inhibit RARα function through PML-dependent aberrant recruitment of histone deacetylases (HDACs) and chromatin remodeling is the key initiating event for leukemogenesis. To elucidate the role of HDAC in this process, we have generated HDAC1–RARα fusion proteins and tested their activity and oncogenicity in vitro and in vivo in transgenic mice (TM). In parallel, we studied the in vivo leukemogenic potential of dominant negative (DN) and truncated RARα mutants, as well as that of PML-RARα mutants that are insensitive to retinoic acid. Surprisingly, although HDAC1-RARα did act as a bona fide DN RARα mutant in cellular in vitro and in cell culture, this fusion protein, as well as other DN RARα mutants, did not cause a block in myeloid differentiation in vivo in TM and were not leukemogenic. Comparative analysis of these TM and of TM/PML−/− and p53−/− compound mutants lends support to a model by which the RARα and PML blockade is necessary, but not sufficient, for leukemogenesis and the PML domain of the fusion protein provides unique functions that are required for leukemia initiation.

scholarly journals Comprehensive genomic screens identify a role for PLZF-RARα as a positive regulator of cell proliferation via direct regulation of c-MYC

Blood ◽  
2009 ◽  
Vol 114 (27) ◽  
pp. 5499-5511 ◽  
Author(s):  
Kim L. Rice ◽  
Itsaso Hormaeche ◽  
Sergei Doulatov ◽  
Jared M. Flatow ◽  
David Grimwade ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Target Genes ◽  
Retinoic Acid Receptor ◽  
Promyelocytic Leukemia ◽  
Dominant Negative ◽  
Myeloid Leukemias ◽  
Direct Target ◽  
Retinoic Acid Receptor Α ◽  
Chip Chip

Abstract The t(11;17)(q23;q21) translocation is associated with a retinoic acid (RA)–insensitive form of acute promyelocytic leukemia (APL), involving the production of reciprocal fusion proteins, promyelocytic leukemia zinc finger–retinoic acid receptor α (PLZF-RARα) and RARα-PLZF. Using a combination of chromatin immunoprecipitation promotor arrays (ChIP-chip) and gene expression profiling, we identify novel, direct target genes of PLZF-RARα that tend to be repressed in APL compared with other myeloid leukemias, supporting the role of PLZF-RARα as an aberrant repressor in APL. In primary murine hematopoietic progenitors, PLZF-RARα promotes cell growth, and represses Dusp6 and Cdkn2d, while inducing c-Myc expression, consistent with its role in leukemogenesis. PLZF-RARα binds to a region of the c-MYC promoter overlapping a functional PLZF site and antagonizes PLZF-mediated repression, suggesting that PLZF-RARα may act as a dominant-negative version of PLZF by affecting the regulation of shared targets. RA induced the differentiation of PLZF-RARα–transformed murine hematopoietic cells and reduced the frequency of clonogenic progenitors, concomitant with c-Myc down-regulation. Surviving RA-treated cells retained the ability to be replated and this was associated with sustained c-Myc expression and repression of Dusp6, suggesting a role for these genes in maintaining a self-renewal pathway triggered by PLZF-RARα.

scholarly journals Cancer Promoted by the Oncoprotein v-ErbA May Be Due to Subcellular Mislocalization of Nuclear Receptors

2005 ◽  
Vol 19 (5) ◽  
pp. 1213-1230 ◽  
Author(s):  
Ghislain M. C. Bonamy ◽  
Anne Guiochon-Mantel ◽  
Lizabeth A. Allison
Keyword(s):  
Transcriptional Regulation ◽  
Nuclear Receptors ◽  
Thyroid Hormone Receptor ◽  
Trichostatin A ◽  
Dominant Negative ◽  
Histone Deacetylase Inhibitor Trichostatin ◽  
Dna Elements ◽  
Dominant Negative Activity ◽  
Thyroid Hormone Receptor Α ◽  
Cellular Compartmentalization

Abstract The retroviral v-ErbA oncoprotein is a highly mutated variant of the thyroid hormone receptor α (TRα), which is unable to bind T3 and interferes with the action of TRα in mammalian and avian cancer cells. v-ErbA dominant-negative activity is attributed to competition with TRα for T3-responsive DNA elements and/or auxiliary factors involved in the transcriptional regulation of T3-responsive genes. However, competition models do not address the altered subcellular localization of v-ErbA and its possible implications in oncogenesis. Here, we report that v-ErbA dimerizes with TRα and the retinoid X receptor and sequesters a significant fraction of the two nuclear receptors in the cytoplasm. Recruitment of TRα to the cytoplasm by v-ErbA can be partially reversed in the presence of ligand and when chromatin is disrupted by the histone deacetylase inhibitor trichostatin A. These results define a new mode of action of v-ErbA and illustrate the importance of cellular compartmentalization in transcriptional regulation and oncogenesis.

scholarly journals Mice Lacking the Calcineurin Inhibitor Rcan2 Have an Isolated Defect of Osteoblast Function

Endocrinology ◽  
2012 ◽  
Vol 153 (7) ◽  
pp. 3537-3548 ◽  
Author(s):  
J. H. Duncan Bassett ◽  
John G. Logan ◽  
Alan Boyde ◽  
Moira S. Cheung ◽  
Holly Evans ◽  
...  
Keyword(s):  
T Cells ◽  
Bone Development ◽  
Skeletal Development ◽  
Dominant Negative ◽  
Nuclear Factor ◽  
Activated T Cells ◽  
Osteoblast Function ◽  
And Function

Calcineurin-nuclear factor of activated T cells signaling controls the differentiation and function of osteoclasts and osteoblasts, and regulator of calcineurin-2 (Rcan2) is a physiological inhibitor of this pathway. Rcan2 expression is regulated by T3, which also has a central role in skeletal development and bone turnover. To investigate the role of Rcan2 in bone development and maintenance, we characterized Rcan2−/− mice and determined its skeletal expression in T3 receptor (TR) knockout and thyroid-manipulated mice. Rcan2−/− mice had normal linear growth but displayed delayed intramembranous ossification, impaired cortical bone formation, and reduced bone mineral accrual during development as well as increased mineralization of adult bone. These abnormalities resulted from an isolated defect in osteoblast function and are similar to skeletal phenotypes of mice lacking the type 2 deiodinase thyroid hormone activating enzyme or with dominant-negative mutations of TRα, the predominant TR isoform in bone. Rcan2 mRNA was expressed in primary osteoclasts and osteoblasts, and its expression in bone was differentially regulated in TRα and TRβ knockout and thyroid-manipulated mice. However, in primary osteoblast cultures, T3 treatment did not affect Rcan2 mRNA expression or nuclear factor of activated T cells c1 expression and phosphorylation. Overall, these studies establish that Rcan2 regulates osteoblast function and its expression in bone is regulated by thyroid status in vivo.

The endocytic adaptor Numb regulates thymus size by modulating pre-TCR signaling during asymmetric division

Blood ◽  
2010 ◽  
Vol 116 (10) ◽  
pp. 1705-1714 ◽  
Author(s):  
Rocio Aguado ◽  
Nadia Martin-Blanco ◽  
Michael Caraballo ◽  
Matilde Canelles
Keyword(s):  
Cell Fate ◽  
Asymmetric Division ◽  
Cell Receptor ◽  
Dominant Negative ◽  
Thymocyte Development ◽  
Tcr Signaling ◽  
Daughter Cells ◽  
Fate Determinants ◽  
Cell Fate Determinants

Abstract Stem cells must proliferate and differentiate to generate the lineages that shape mature organs; understanding these 2 processes and their interaction is one of the central themes in current biomedicine. An intriguing aspect is asymmetric division, by which 2 daughter cells with different fates are generated. Several cell fate determinants participate in asymmetric division, with the endocytic adaptor Numb as the best-known example. Here, we have explored the role of asymmetric division in thymocyte development, visualizing the differential segregation of Numb and pre-TCR in thymic precursors. Analysis of mice where Numb had been inhibited by expressing a dominant negative revealed enhanced pre–T-cell receptor (TCR) signaling and a smaller thymus. Conversely, Numb overexpression resulted in loss of asymmetric division and a larger thymus. The conclusion is that Numb determines the levels of pre-TCR signaling in dividing thymocytes and, ultimately, the size of the pool from which mature T lymphocytes are selected.

scholarly journals Retinoid X Receptor (RXR) Agonist-Induced Activation of Dominant-Negative RXR-Retinoic Acid Receptor α403 Heterodimers Is Developmentally Regulated during Myeloid Differentiation

1999 ◽  
Vol 19 (5) ◽  
pp. 3372-3382 ◽  
Author(s):  
Barton S. Johnson ◽  
Roshantha A. S. Chandraratna ◽  
Richard A. Heyman ◽  
Elizabeth A. Allegretto ◽  
LeMoyne Mueller ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Trichostatin A ◽  
Receptor Activation ◽  
Nuclear Hormone Receptor ◽  
Retinoid X Receptor ◽  
Dominant Negative ◽  
Mouse Bone Marrow ◽  
Granulocytic Differentiation ◽  
Response Elements ◽  
Dominant Negative Activity

ABSTRACT The multiple biologic activities of retinoic acid (RA) are mediated through RAR and retinoid X receptor (RXR) nuclear receptors that interact with specific DNA target sequences as heterodimers (RXR-RAR) or homodimers (RXR-RXR). RA receptor activation appears critical to regulating important aspects of hematopoiesis, since transducing a COOH-terminally truncated RARα exhibiting dominant-negative activity (RARα403) into normal mouse bone marrow generates hematopoietic growth factor-dependent cell lines frozen at the multipotent progenitor (EML) or committed promyelocyte (MPRO) stages. Nevertheless, relatively high, pharmacological concentrations of RA (1 to 10 μM) overcome these differentiation blocks and induce terminal granulocytic differentiation of the MPRO promyelocytes while potentiating interleukin-3 (IL-3)-induced commitment of EML cells to the granulocyte/monocyte lineage. In the present study, we utilized RXR- and RAR-specific agonists and antagonists to determine how RA overcomes the dominant-negative activity of the truncated RARα in these different myeloid developmental stages. Unexpectedly, we observed that an RXR-specific, rather than an RAR-specific, agonist induces terminal granulocytic differentiation of MPRO promyelocytes, and this differentiation is associated with activation of DNA response elements corresponding to RAR-RXR heterodimers rather than RXR-RXR homodimers. This RXR agonist activity is blocked by RAR-specific antagonists, suggesting extensive cross-talk between the partners of the RXR-RARα403 heterodimer. In contrast, in the more immature, multipotent EML cells we observed that this RXR-specific agonist is inactive either in potentiating IL-3-mediated commitment of EML cells to the granulocyte lineage or in transactivating RAR-RXR response elements. RA-triggered GALdbd-RARα hybrid activity in these cells indicates that the multipotent EML cells harbor substantial nuclear hormone receptor coactivator activity. However, the histone deacetylase (HDAC) inhibitor trichostatin A readily activates an RXR-RAR reporter construct in the multipotent EML cells but not in the committed MPRO promyelocytes, indicating that differences in HDAC-containing repressor complexes in these two closely related but distinct hematopoietic lineages might account for the differential activation of the RXR-RARα403 heterodimers that we observed at these different stages of myeloid development.

An essential role for retinoid signaling in anteroposterior neural patterning

Development ◽  
1997 ◽  
Vol 124 (2) ◽  
pp. 373-379 ◽  
Author(s):  
B. Blumberg ◽  
J. Bolado ◽  
T.A. Moreno ◽  
C. Kintner ◽  
R.M. Evans ◽  
...  
Keyword(s):  
Dominant Negative ◽  
Marker Genes ◽  
Neural Patterning ◽  
Retinoid Signaling ◽  
Retinoid Receptors ◽  
Neural Fate ◽  
Dorsal Mesoderm ◽  
Neural Ectoderm ◽  
Vertebrate Central Nervous System

The vertebrate central nervous system (CNS) is induced by signals emanating from the dorsal mesoderm, or organizer, that divert the ectoderm away from an epidermal and towards a neural fate. Additional signals from the organizer pattern the neural ectoderm along the anteroposterior axis. We devised highly specific methods utilizing constitutively active or dominant negative receptors to evaluate the role of retinoids in neural patterning. Microinjection of these reagents either augments or reduces retinoid signaling in specific regions of the embryo. We show that increased receptor activity suppresses anterior neural structures while dominant negative receptors lead to anterior enhancement. Similarly, microinjection of the dominant negative receptor leads to the loss of posterior marker genes. We demonstrate that retinoid receptors comprise a critical component in neural posteriorization and are required for proper neuronal differentiation. These results support a quantitative role for retinoid signaling in regionalization of the CNS.

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