Molecular approaches to vertebrate limb morphogenesis

Development ◽  
1989 ◽  
Vol 107 (Supplement) ◽  
pp. 121-131 ◽  
Author(s):  
Susan M. Smith ◽  
Kevin Pang ◽  
Olof Sundin ◽  
Sarah E. Wedden ◽  
Christina Thaller ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Cell Fate ◽  
Retinoic Acid Receptor ◽  
Active Form ◽  
Mirror Image ◽  
Biologically Active ◽  
Molecular Approaches ◽  
Limb Morphogenesis ◽  
Order Of Magnitude ◽  
Temporal Expression Pattern

It has long been proposed that concentration gradients of morphogens provide cues to specify cell fate in embryonic fields. Recent work in a variety of vertebrate systems give bona fide evidence that retinoic acid, the biologically active form of vitamin A, is a candidate for such a morphogen. In the developing chick wing, for example, locally applied retinoic acid triggers striking changes in the pattern along the anteroposterior axis. Instead of giving rise to a wing with the normal 234 digit pattern, wing buds treated with retinoic acid develop a 432234 mirror-image symmetrical digit pattern. For this review, we focus on three aspects of limb morphogenesis. (1) We summarize the experimental evidence supporting the notion that retinoic acid is a candidate morphogen. (2) Limb buds contain high levels of cellular retinoic-acid-binding protein (CRABP). Using order of magnitude calculations, we evaluate how the concentration of CRABP might affect the occupancy state of the retinoic acid receptor. (3) We discuss the spatio-temporal expression pattern of homeobox-containing genes in the developing limb and speculate about the possibility that retinoic acid influences the pattern of expression of homeobox genes.

scholarly journals Attenuation of Hypertrophy in Human MSCs via Treatment with a Retinoic Acid Receptor Inverse Agonist

2020 ◽  
Vol 21 (4) ◽  
pp. 1444 ◽  
Author(s):  
Moritz Riedl ◽  
Christina Witzmann ◽  
Matthias Koch ◽  
Siegmund Lang ◽  
Maximilian Kerschbaum ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Cell Fate ◽  
Limb Development ◽  
Retinoic Acid Receptor ◽  
Cartilage Regeneration ◽  
Inverse Agonist ◽  
Cartilage Tissue ◽  
Human Mscs ◽  
Acid Receptor

In vitro chondrogenically differentiated mesenchymal stem cells (MSCs) have a tendency to undergo hypertrophy, mirroring the fate of transient “chondrocytes” in the growth plate. As hypertrophy would result in ossification, this fact limits their use in cartilage tissue engineering applications. During limb development, retinoic acid receptor (RAR) signaling exerts an important influence on cell fate of mesenchymal progenitors. While retinoids foster hypertrophy, suppression of RAR signaling seems to be required for chondrogenic differentiation. Therefore, we hypothesized that treatment of chondrogenically differentiating hMSCs with the RAR inverse agonist, BMS204,493 (further named BMS), would attenuate hypertrophy. We induced hypertrophy in chondrogenic precultured MSC pellets by the addition of bone morphogenetic protein 4. Direct activation of the RAR pathway by application of the physiological RAR agonist retinoic acid (RA) further enhanced the hypertrophic phenotype. However, BMS treatment reduced hypertrophic conversion in hMSCs, shown by decreased cell size, number of hypertrophic cells, and collagen type X deposition in histological analyses. BMS effects were dependent on the time point of application and strongest after early treatment during chondrogenic precultivation. The possibility of modifing hypertrophic cartilage via attenuation of RAR signaling by BMS could be helpful in producing stable engineered tissue for cartilage regeneration.

Evidence that Shh cooperates with a retinoic acid inducible co-factor to establish ZPA-like activity

Development ◽  
1996 ◽  
Vol 122 (2) ◽  
pp. 537-542 ◽  
Author(s):  
T. Ogura ◽  
I.S. Alvarez ◽  
A. Vogel ◽  
C. Rodriguez ◽  
R.M. Evans ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Sonic Hedgehog ◽  
Embryonal Carcinoma ◽  
Carcinoma Cell ◽  
Retinoic Acid Receptor ◽  
Mirror Image ◽  
Limb Bud ◽  
Embryonal Carcinoma Cell ◽  
Embryonal Carcinoma Cell Line ◽  
Vertebrate Limb

Patterning across the anteroposterior axis of the vertebrate limb bud involves a signal from the polarizing region, a small group of cells at the posterior margin of the bud. Retinoic acid (RA; Tickle, C., Alberts, B., Wolpert, L. and Lee, J. (1982) Nature 296, 554–566) and Sonic hedgehog (Shh; Riddle, R. D. Johnson, R. L., Laufer, E. and Tabin, C. J. (1993) Cell 25, 1401–1416; Chang, D. T., Lopez, A., von Kessler, D. P., Chiang, C., Simandl, B. K., Zhao, R., Seldin, M. F., Fallon, J. F. and Beachy, P. A. (1994 Development 120, 3339–3353) have been independently postulated as such signals because they can mimic the mirror image digit duplication obtained after grafting polarizing cells to the anterior of limb buds. Here we show that a embryonal carcinoma cell line, P19, transfected with a Shh expression vector shows low polarizing activity, but when cultured with retinoic acid, duplications like those induced by the polarizing region (ZPA) arise. Complete duplications are also obtained by cotransfecting P19 Shh cells with a constitutively active human retinoic acid receptor (VP16-hRARalpha). These data suggest that Shh and RA cooperate in generating ZPA activity and that Shh, while essential, may not act alone in this process.

scholarly journals A biologically active metabolite of retinoic acid from rat liver

1965 ◽  
Vol 97 (1) ◽  
pp. 180-186 ◽  
Author(s):  
M Zile ◽  
HF Deluca
Keyword(s):  
Retinoic Acid ◽  
Methyl Ester ◽  
Vitamin A ◽  
Active Metabolite ◽  
Active Form ◽  
Active Material ◽  
Biologically Active ◽  
Growth Assay ◽  
Hydrolysis Of ◽  
Acidic Compound

1. Four major radioactive fractions have been isolated from the livers of vitamin A-deficient rats given [6,7-(14)C(2)]retinoic acid. 2. At least one of these was more potent than retinoic acid and approximately equal to retinol in the growth assay for vitamin A activity. 3. The biologically active material was chromatographically distinct from retinoic acid, retinol and retinal. 4. Alkaline hydrolysis of this material yielded an acidic compound containing all the radioactivity. 5. The methyl ester of the acidic product was unlike the methyl ester of retinoic acid in its chromatographic behaviour. 6. It is suggested that this metabolite may represent the active form of retinol in its growth-supporting role.

scholarly journals Potentiation of GATA-2 Activity through Interactions with the Promyelocytic Leukemia Protein (PML) and the t(15;17)-Generated PML-Retinoic Acid Receptor α Oncoprotein

2000 ◽  
Vol 20 (17) ◽  
pp. 6276-6286 ◽  
Author(s):  
Shinobu Tsuzuki ◽  
Masayuki Towatari ◽  
Hidehiko Saito ◽  
Tariq Enver
Keyword(s):  
Retinoic Acid ◽  
Cell Fate ◽  
Target Genes ◽  
Retinoic Acid Receptor ◽  
Promyelocytic Leukemia ◽  
Promyelocytic Leukemia Protein ◽  
Acid Receptor ◽  
Survival And Growth ◽  
Retinoic Acid Receptor Α ◽  
Zinc Finger Region

ABSTRACT The hematopoietically expressed GATA family of transcription factors function as key regulators of blood cell fate. Among these, GATA-2 is implicated in the survival and growth of multipotential progenitors. Here we report that the promyelocytic leukemia protein (PML) can complex with GATA-2 and potentiate its transactivation capacity. The binding is mediated through interaction of the zinc finger region of GATA-2 and the B-box domain of PML. The B-box region of PML is retained in the PML-RARα (retinoic acid receptor alpha) fusion protein generated by the t(15;17) translocation characteristic of acute promyelocytic leukemia (APL). Consistent with this, we provide evidence that GATA-2 can physically associate with PML-RARα. Functional experiments further demonstrated that this interaction has the capacity to render GATA-dependent transcription inducible by retinoic acid, raising the possibility that GATA target genes may be involved in the molecular pathogenesis of APL.

scholarly journals Spatial and temporal expression pattern of retinoic acid receptor genes during mouse bone development

FEBS Letters ◽  
1989 ◽  
Vol 257 (1) ◽  
pp. 93-96 ◽  
Author(s):  
Sumihare Noji ◽  
Tomoichiro Yamaai ◽  
Eiki Koyama ◽  
Tsutomu Nohno ◽  
Shigehiko Taniguchi
Keyword(s):  
Retinoic Acid ◽  
Expression Pattern ◽  
Bone Development ◽  
Retinoic Acid Receptor ◽  
Temporal Expression ◽  
Acid Receptor ◽  
Temporal Expression Pattern

scholarly journals The role of retinoic acid receptors and their cognate ligands in reproduction in a context of triorganotin based endocrine disrupting chemicals

2016 ◽  
Vol 50 (3) ◽  
pp. 154-164 ◽  
Author(s):  
Dana Macejova ◽  
L. Toporova ◽  
J. Brtko
Keyword(s):  
Retinoic Acid ◽  
Nuclear Receptors ◽  
Active Form ◽  
Biologically Active ◽  
Organotin Compounds ◽  
Female Reproduction ◽  
Transcriptional Responses ◽  
Male And Female ◽  
Tributyltin Chloride ◽  
Endocrine Disrupting

Abstract Retinoic acid (RA), an active form of vitamin A, regulates the embryonic development, male and female reproduction and induces important effects on the cell development, proliferation, and differentiation. These effects are mediated by the retinoid (RAR) and rexinoid nuclear receptors (RXR), which are considered to be a ligand-activated, DNA-binding, trans-acting, and transcription-modulating proteins, involved in a general molecular mechanism responsible for the transcriptional responses in target genes. Organotin compounds are typical environmental contaminants and suspected endocrine disrupting substances. They may affect processes of reproductive system in mammals, predominantly via nuclear receptor signaling pathways. Triorganotins, such as tributyltin chloride (TBTCl) and triphenyltin chloride (TPTCl), are capable to bind to RXR molecules, and thus represent potent agonists of RXR subtypes of nuclear receptors not sharing any structural characteristics with endogenous ligands of nuclear receptors. Th is article summarizes selected effects of biologically active retinoids and rexinoids on both male and female reproduction and also deals with the effects of organotin compounds evoking endocrine disrupting actions in reproduction.

Processing and Characterization of Recombinant von Willebrand Factor Expressed in Different Cell Types Using a Vaccinia Virus Vector

1992 ◽  
Vol 67 (01) ◽  
pp. 154-160 ◽  
Author(s):  
P Meulien ◽  
M Nishino ◽  
C Mazurier ◽  
K Dott ◽  
G Piétu ◽  
...  
Keyword(s):  
Vaccinia Virus ◽  
Von Willebrand Factor ◽  
Human Fibroblasts ◽  
Active Form ◽  
Cell Types ◽  
Biologically Active ◽  
L Cells ◽  
Von Willebrand ◽  
Different Cell Types ◽  
Willebrand Factor

SummaryThe cloning of the cDNA encoding von Willebrand factor (vWF) has revealed that it is synthesized as a large precursor (pre-pro-vWF) molecule and it is now clear that the prosequence or vWAgll is responsible for the intracellular multimerization of vWF. We have cloned the complete vWF cDNA and expressed it using a recombinant vaccinia virus as vector. We have characterized the structure and function of the recombinant vWF (rvWF) secreted from five different cell types: baby hamster kidney (BHK), Chinese hamster ovary (CHO), human fibroblasts (143B), mouse fibroblasts (L) and primary embryonic chicken cells. Forty-eight hours after infection, the quantity of vWF antigen found in the cell supernatant varied from 3 to 12 U/dl depending on the cell type. By SDS-agarose gel electrophoresis, the percentage of high molecular weight forms of vWF varied from 39 to 49% relative to normal plasma for BHK, CHO, 143B and chicken cells but was less than 10% for L cells. In all cell types, the two anodic subbands of each multimer were missing. The two cathodic subbands were easily detected only in BHK and L cells. By SDS-PAGE of reduced samples, pro-vWF was present in similar quantity to the fully processed vWF subunit in L cells, present in moderate amounts in BHK and CHO and in very low amounts in 143B and chicken cells. rvWF from all cells bound to collagen and to platelets in the presence of ristocetin, the latter showing a high correlation between binding efficiency and degree of multimerization. rvWF from all cells was also shown to bind to purified FVIII and in this case binding appeared to be independent of the degree of multimerization. We conclude that whereas vWF is naturally synthesized only by endothelial cells and megakaryocytes, it can be expressed in a biologically active form from various other cell types.

Contribution of retinoic acid receptor signalling to adrenal cortex morphology and functional zonation through modulation of WNT/[beta]-catenin pathway

2017 ◽  
Author(s):  
Zein Rami El ◽  
Amanda J Rickard ◽  
Golib Dzib Jose Felipe ◽  
Benoit Samson-Couterie ◽  
Angelique Rocha ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Adrenal Cortex ◽  
Retinoic Acid Receptor ◽  
Beta Catenin ◽  
Acid Receptor ◽  
Receptor Signalling

Innovative approaches to the correction of chronotrope status of pregnant and lactating women

2016 ◽  
pp. 37-40
Author(s):  
S.I. Zhuk ◽  
◽  
K.K. Bondarenko ◽  
Keyword(s):  
Folic Acid ◽  
Neural Tube ◽  
Active Form ◽  
Biologically Active ◽  
Lactating Women ◽  
Pathological Conditions ◽  
Prevention And Treatment ◽  
The Impact ◽  
High Bioavailability ◽  
Key Words Mthfr

Most recent studies show the impact of violations in the metabolism of folate and metin period in the pathogenesis of neural tube defects (NTD) of the fetus. Metafolin has a number of advantages, which primarily includes direct intake of substances in biologically active form and the optimum effect, even in the case when the patient homozygote and/or heterozygote genotype 677С T polymorphism in MTHFR. With the aim of prevention and treatment of various pathological conditions related to folate deficiency during pregnancy, it is advisable to apply vitamin-mineral complexes, containing metafolin - active form of folate with high bioavailability. Key words: MTHFR, metafolin, folic acid, pregnancy.

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