Domains of retinoid signalling and neurectodermal expression of zebrafish otx1 and goosecoid are mutually exclusive

1997 ◽  
Vol 75 (5) ◽  
pp. 601-612 ◽  
Author(s):  
Jos Joore ◽  
Ans Timmermans ◽  
Sandra de van Water ◽  
Gert E Folkers ◽  
Paul T van der Saag ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Target Genes ◽  
Retinoic Acid Receptor ◽  
Zebrafish Embryos ◽  
Transactivation Domain ◽  
Anteroposterior Patterning ◽  
Axial Defects ◽  
Embryonic Shield ◽  
Novel Method

Retinoid signalling plays an important role in embryonic pattern formation. Excess of retinoic acid during gastrulation results in axial defects in vertebrate embryos, suggesting that retinoids are involved in early anteroposterior patterning. To study retinoid signalling in zebrafish embryos, we developed a novel method to detect endogenous retinoids in situ in embryos, using a fusion protein of the ligand inducible transactivation domain of a retinoic acid receptor and a heterologous DNA binding domain. Using this method, we show that retinoid signalling is localized in zebrafish embryos in the region of the embryonic shield, and towards the end of gastrulation in a posterior dorsal domain. To investigate the relationships between the spatial distribution of retinoid signalling and the regulation of retinoid target genes, we studied the downregulation by retinoic acid of two genes expressed in anterior regions of the embryo, goosecoid and otx1. These experiments show that expression of both genes is strongly downregulated in the anterior neurectoderm of zebrafish embryos treated with retinoic acid, whereas mesendodermal expression is only mildly affected. Interestingly, a significant downregulation of goosecoid expression by retinoic acid was observed only during midgastrulation but not in earlier stages. In agreement with these results, spatial expression of goosecoid and otx1 does not overlap with the region of retinoid signalling in the late gastrula. Our data support the hypothesis that a localized retinoid signal is involved in axial patterning during early development, at least in part through the repression of anterior genes in posterior regions of the embryo. Furthermore, our data suggest that the action of retinoids is spatially as well as temporally regulated in the developing embryo.

Temporal and regional differences in the expression pattern of distinct retinoic acid receptor-beta transcripts in the chick embryo

Development ◽  
1991 ◽  
Vol 111 (1) ◽  
pp. 245-252 ◽  
Author(s):  
S.M. Smith ◽  
G. Eichele
Keyword(s):  
Retinoic Acid ◽  
In Situ Hybridization ◽  
Expression Pattern ◽  
Target Genes ◽  
Retinoic Acid Receptor ◽  
Receptor Gene ◽  
Regulatory Region ◽  
Limb Bud ◽  
Differential Distribution

Retinoic acid (RA) is a signaling molecule apparently involved in a variety of morphogenetic processes, such as patterning of developing and regenerating vertebrate limbs. RA binds to specific intracellular receptors that constitute a multigene family. RA receptors (RAR) bind to the regulatory region of specific target genes and thereby control the expression of these genes. Here we report the sequence and spatiotemporal expression pattern of RAR-beta from chick. Northern blots of RNA from whole embryos and from limb buds reveal the presence of transcripts of 3.2, 3.4, and 4.6 kb in size. Using two riboprobes, one that hybridizes to all three RAR-beta mRNAs and a second one, specific for the 4.6 kb transcript, we found by in situ hybridization a differential distribution of RAR-beta transcripts in limb bud mesenchyme, in craniofacial mesenchyme and in hindbrain neuroectoderm. In the hindbrain the 4.6 kb mRNA exhibits an anterior boundary of expression at the level of the constriction between rhombomeres 5 and 6. Examination of neural plate stage embryos by in situ hybridization indicates that this boundary of expression is already defined by this stage. In addition to having several RA receptors that are expressed with distinct spatial patterns in the embryo, our data indicate that the expression pattern of transcripts derived from a single receptor gene can also be differentially expressed, thus providing another level for regulating RA action.

Development of the spatial pattern of retinoic acid receptor-beta transcripts in embryonic chick facial primordia

Development ◽  
1992 ◽  
Vol 114 (3) ◽  
pp. 805-813
Author(s):  
A. Rowe ◽  
J.M. Richman ◽  
P.M. Brickell
Keyword(s):  
Retinoic Acid ◽  
Neural Crest ◽  
Retinoic Acid Receptor ◽  
In Situ Hybridisation ◽  
Acid Receptor ◽  
Retinoic Acid Receptor Beta ◽  
Low Levels ◽  
Cranial Neural Crest Cells ◽  
Receptor Beta

Retinoic acid causes a range of embryonic defects, including craniofacial abnormalities, in both birds and mammals and is believed to have a number of roles in normal development. We have previously shown that the distribution of retinoic acid receptor-beta (RAR-beta) transcripts is spatially restricted within the neural-crest-derived upper beak primordia of the chick embryo. We have now used in situ hybridisation to trace the distribution of RAR-beta transcripts during the migration of cranial neural crest cells and during formation of these primordia. RAR-beta transcripts were present in a subset of migrating neural-crest-derived cells in the head of the stage 10 embryo. These cells were situated in pathways followed by cells that migrate from the neural crest overlying the posterior prosencephalic/anterior mesencephalic region of the developing brain. Cells containing RAR-beta transcripts accumulated around the developing eyes and in the regions of the ventral head from which the upper beak primordia later develop. We mapped the distribution of RAR-beta transcripts as the facial primordia were forming, with particular reference to the development of the maxillary primordia. We found that these form in a region of the ventral head that includes the boundary between regions of high and low levels of RAR-beta transcripts. The boundary between these two groups of cells persisted as the maxillary primordia developed.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

Mutation of Cellular Retinoic Acid-Binding Protein-II (Crabp-II) Does Not Account for Resistance to All-Trans Retinoic Acid (ATRA) in Relapse Acute Promyelocytic Leukemia (APL).

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2081-2081
Author(s):  
Binu-John Sankoorikal ◽  
Da-Cheng Zhou ◽  
Peter H. Wiernik ◽  
Robert E. Gallagher
Keyword(s):  
Retinoic Acid ◽  
Target Genes ◽  
Retinoic Acid Receptor ◽  
Treated Patient ◽  
Coding Region ◽  
Treatment Regimens ◽  
All Trans Retinoic Acid ◽  
Negative Role ◽  
Multiple Relapse ◽  
Crabp Ii

Abstract An increase in CRABP-II has frequently been invoked as a cause of resistance to ATRA in APL due to cytoplasmic sequestration and catabolism of ATRA. However, recent evidence indicates that CRABP-II has a positive rather than a negative role in ATRA activity by facilitating delivery of ATRA to retinoic acid receptor-alpha (RARα) associated with ATRA target genes in the cell nucleus or/and by serving as a co-activator of RARα-regulated transcription. This implies that if CRABP-II has a role in the development of ATRA resistance in APL, this would more likely occur through a deficiency rather than from an increase in CRABP-II. We previously reported that CRABP-II is constitutively expressed at similar levels in pretreatment and relapse APL cells (Zhou, et al, Cancer Res58, 5770, 1998), suggesting that putative CRABP-II deficiency is not due to the loss of CRABP-II expression. To investigate the alternative possibility that CRABP-II deficiency might arise through inactivating mutations, we sequenced the entire coding region of CRABP-II from 18 cases of APL who had relapsed from prior ATRA-containing treatment regimens. In 8 cases RNA was transcribed by reverse transcriptase to cDNA and amplified by polymerase chain reaction (PCR), using primers anchored in the 5′ and 3′ untranslated region of mRNA; in 10 cases, genomic DNA was PCR amplified for sequence analysis, using primers anchored in the introns between the 4 exons of the gene. No CRABP-II mutations were identified. The samples tested included 11 first-relapse cases, 2 of whom were refractory to reinduction therapy with intravenous liposomal-ATRA, and 7 multiple relapse cases, all of whom were clinically refractory to ATRA and had, additionally, relapsed from arsenic trioxide therapy. Also, no mutations were found in 3 APL patients who had relapsed from chemotherapy-induced remissions or in 3 APL cell lines (NB4, UF-1 and AP-1060). Two heterozygous base substitutions were incidentally identified in CRABP-II intron 2 in a chemotherapy-only treated patient. These results indicate that CRABP-II mutations rarely, if ever, contribute to ATRA-resistance or disease relapse in APL.

scholarly journals Ligands and DNA in the allosteric control of retinoid receptors function

2021 ◽  
Author(s):  
Pierre Germain ◽  
Natacha Rochel ◽  
William Bourguet
Keyword(s):  
Retinoic Acid ◽  
Dna Sequences ◽  
Target Genes ◽  
Retinoic Acid Receptor ◽  
Signal Propagation ◽  
Retinoid Receptors ◽  
Allosteric Control ◽  
Current State ◽  
All Trans Retinoic Acid ◽  
Structural Mechanisms

Abstract Retinoids are a family of compounds that include both vitamin A (all-trans retinol) and its naturally occurring metabolites such as retinoic acids (e.g. all-trans retinoic acid) as well as synthetic analogs. They are critically involved in the regulation of a wide variety of essential biological processes, such as embryogenesis and organogenesis, apoptosis, reproduction, vision, and the growth and differentiation of normal and neoplastic cells in vertebrates. The ability of these small molecules to control the expression of several hundred genes through binding to nuclear ligand-dependent transcription factors accounts for most of their functions. Three retinoic acid receptor (RARα,β,γ) and three retinoid X receptor (RXRα,β,γ) subtypes form a variety of RXR–RAR heterodimers that have been shown to mediate the pleiotropic effects of retinoids through the recruitment of high-molecular weight co-regulatory complexes to response-element DNA sequences found in the promoter region of their target genes. Hence, heterodimeric retinoid receptors are multidomain entities that respond to various incoming signals, such as ligand and DNA binding, by allosteric structural alterations which are the basis of further signal propagation. Here, we provide an overview of the current state of knowledge with regard to the structural mechanisms by which retinoids and DNA response elements act as allosteric effectors that may combine to finely tune RXR–RAR heterodimers activity.

Specific spatial and temporal distribution of retinoic acid receptor gamma transcripts during mouse embryogenesis

Development ◽  
1990 ◽  
Vol 108 (2) ◽  
pp. 213-222 ◽  
Author(s):  
E. Ruberte ◽  
P. Dolle ◽  
A. Krust ◽  
A. Zelent ◽  
G. Morriss-Kay ◽  
...  
Keyword(s):  
Gene Expression ◽  
Retinoic Acid ◽  
Retinoic Acid Receptor ◽  
Temporal Distribution ◽  
Spatial And Temporal Distribution ◽  
Mouse Development ◽  
Pharyngeal Arches ◽  
Acid Receptor ◽  
Squamous Epithelia

Retinoic acid (RA), a putative morphogen in vertebrates, has profound effects on development during embryogenesis, chondrogenesis and differentiation of squamous epithelia. The distribution of the transcripts of the retinoic acid receptor gamma (RAR-gamma) gene has been studied here by in situ hybridization during mouse development from days 6.5 to 15.5 post-coitum (p.c.). RAR-gamma transcripts are detected as early as day 8 p.c. in the presomitic posterior region. Between days 9.5 and 11.5 p.c., the transcripts are uniformly distributed in the mesenchyme of the frontonasal region, pharyngeal arches, limb buds and sclerotomes. At day 12.5 p.c., RAR-gamma transcripts are found in all precartilaginous mesenchymal condensations. From day 13.5 p.c., the transcripts are specifically localized in all cartilages and differentiating squamous keratinizing epithelia, irrespective of their embryological origin. RAR-gamma transcripts are also found in the developing teeth and whisker follicles. The developmental pattern of expression of the RAR-gamma gene suggests that RAR-gamma plays a crucial role for transducing RA signals at the level of gene expression during morphogenesis, chondrogenesis and differentiation of squamous epithelia.

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