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Abstract 1. 1. The epinephrine and norepinephrine content of plasma of Nembutal-anesthetized rats in various thyroid states was determined. One liter of plasma from normal rats had 6.2 μg. norepinephrine and 0.9 μg. epinephrine. One liter... more
Abstract 1. 1. The epinephrine and norepinephrine content of plasma of Nembutal-anesthetized rats in various thyroid states was determined. One liter of plasma from normal rats had 6.2 μg. norepinephrine and 0.9 μg. epinephrine. One liter of plasma from thyroidectomized rats had 6.7 μg. norepinephrine and 2.1 μg. epinephrine. Plasma from thyroid-fed animals had 12.0 μg. norepinephrine and 4.0 μg. epinephrine per liter. 2. 2. A comparison of hepatic mitochondrial monoamine oxidase activity of rats in different thyroid states revealed that mitochondria from normal rats oxidized tyramine twice as fast as did those from rats fed thyroid substance. 3. 3. Monoamine oxidase activity declined steadily during thyroid feeding and was restored to normal levels after discontinuing the treatment. 4. 4. Evidence is presented that the decreased monoamine oxidase activity in the liver of thyroid-fed rats is not due to direct inhibition of the enzyme by thyroid hormone or other inhibitors in the tissue. 5. 5. The monoamine oxidase is distributed among the various cellular components in the same relative amounts in livers of thyroid-fed rats as in normal rats. 6. 6. Partial solubilization of monoamine oxidase resulted after sonation of acetone-dried hepatic mitochondria.
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Research Interests: Biology, Cell Biology, Transcription Factors, Morphogenesis, In Situ Hybridization, and 14 moreSignal Transduction, Embryo, Biological Sciences, Animals, RETINOIDS, Phenotype, Myocardium, Time Factors, Retinoic Acid, Retinoid, Cell Survival, DNA binding proteins, retinoid X receptor, and Medical and Health Sciences
Research Interests: Developmental Biology, Biology, Transcription Factors, Medicine, Gene expression, and 15 moreBiological Sciences, Mice, Animals, Early development, Enzyme, Retinoic Acid, Vitamin A deficiency, Tretinoin, Retinoid, Embryos, Fetal death, retinoid X receptor, Retinoic Acid Receptor, Medical and Health Sciences, and Expression pattern
... Regular Article. Retinoid Signaling Is Required to Complete the Vertebrate Cardiac Left/Right Asymmetry Pathway *1. Maija H. Zile a , 1 , Igor Kostetskii a , Saying Yuan a , Ekaterina Kostetskaia a , Tara R. St. ... Virchows Arch.... more
... Regular Article. Retinoid Signaling Is Required to Complete the Vertebrate Cardiac Left/Right Asymmetry Pathway *1. Maija H. Zile a , 1 , Igor Kostetskii a , Saying Yuan a , Ekaterina Kostetskaia a , Tara R. St. ... Virchows Arch. (Cell Pathol.) 50 (1985), pp. 135152. ...
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Research Interests: Endocrinology, Biology, Morphogenesis, Development, Medicine, and 13 moreEmbryo, Internal Medicine, Animals, Heart Development, Heart, Retinoic Acid, Transforming Growth Factor Beta, Vitamin A deficiency, Tretinoin, Quail, Biochemistry and cell biology, Transforming Growth Factor, and Paediatrics and reproductive medicine
Research Interests: Biology, Cell Biology, Morphogenesis, Medicine, Biological Sciences, and 15 moreAnimals, Embryonic Stem Cell, Plant tissue Culture Techniques, Heart Development, Heart, Myocardium, Chickens, In vitro culture, Retinoic Acid, TGFβ, Enzyme Linked Immunosorbent Assay, reverse transcriptase polymerase chain reaction, Tissue culture techniques, Chick embryo, and Medical and Health Sciences
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We examined the effect of vitamin A nutritional status on cell division in various epithelial tissues of the rat. Tissues were examined by histological methods, and DNA labeling was assessed by autoradiography. Mild vitamin A deficiency... more
We examined the effect of vitamin A nutritional status on cell division in various epithelial tissues of the rat. Tissues were examined by histological methods, and DNA labeling was assessed by autoradiography. Mild vitamin A deficiency decreased the DNA labeling index in the trachea and the epidermis, while not altering the histological appearance of the tissue. In some tracheae, foci of hyperplasia were present. The histological appearance and the DNA labeling index of the cornea, jejunum and colon were not altered by mild vitamin A deficiency. We concluded that a diminished proliferation of epithelial cells is a manifestation of suboptimal vitamin A availability in that tissue.
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The potential of all-trans-5,6-epoxyretinoic acid to promote growth in vitamin A-deficient rats was evaluated over a 25-fold dose range using single daily intraperitoneal injections. 5,6-Epoxyretinoic acid was found to be 0.5% as active... more
The potential of all-trans-5,6-epoxyretinoic acid to promote growth in vitamin A-deficient rats was evaluated over a 25-fold dose range using single daily intraperitoneal injections. 5,6-Epoxyretinoic acid was found to be 0.5% as active as all-trans-retinoic acid. The discrepancies between the present results and those obtained previously by other workers are discussed.
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Cell division kinetics and the biochemical composition of the small intestine of normal and mildly vitamin A-deficient rats have been examined. Thymidine labeling index, growth fraction and the content of DNA, RNA and protein in the... more
Cell division kinetics and the biochemical composition of the small intestine of normal and mildly vitamin A-deficient rats have been examined. Thymidine labeling index, growth fraction and the content of DNA, RNA and protein in the jejunal mucosa were not significantly affected by vitamin A deficiency. On the other hand, the duration of the cell cycle of jejunal crypt cells was found to be lengthened by vitamin A deficiency and this increase in generation time was due mainly to a lengthening of the DNA synthesis phase. Furthermore, the labeling pattern of the newly divided crypt cells of the vitamin A-deficient rats was strikingly different from that of the vitamin A-supplemented rats, suggesting an impaired migration of cells out of the crypts. These findings suggest that vitamin A may play a role in the regulation of cell division in the small intestine of the rat.
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Vitamin A deficiency had no effect on serum calcium levels but decreased markedly the urinary excretion of calcium. Creatinine clearance and urinary protein levels were not altered by vitamin A deficiency. The decrease in urinary calcium... more
Vitamin A deficiency had no effect on serum calcium levels but decreased markedly the urinary excretion of calcium. Creatinine clearance and urinary protein levels were not altered by vitamin A deficiency. The decrease in urinary calcium occurred very early in the depletion period and was rapidly re stored to normal by retinol administration. It is suggested that the urinary cal
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Several metabolites detected in the bile of rats given radioactive retinoic acid were separated by liquid/gel partition chromatography and purified by high-pressure liquid chromatography. One of these metabolites was found to be sensitive... more
Several metabolites detected in the bile of rats given radioactive retinoic acid were separated by liquid/gel partition chromatography and purified by high-pressure liquid chromatography. One of these metabolites was found to be sensitive to beta-D-glucuronidase, yielding both 13-cis- and all-trans-retinoic acid. It had the characteristic ultraviolet absorption spectrum of retinoic acid esters. Trimethylsilyl ether and acetyl derivatives of the methylated metabolite were prepared and examined by mass spectrometry. The resulting mass spectra established the structure to be retinoyl beta-glucuronide. Retinoyl glucuronide was rapidly excreted into the bile: the excretion was complete by 12 hr after the administration of retinoic acid. At this time the metabolite represented 12% of bile radioactivity (10% of dose). These observations confirm the existence of retinoyl glucuronide but demonstrate that it represents only one of several retinoic acid metabolites in bile.
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Research Interests: Chemistry, Analytical Chemistry, Chromatography, Medicine, Lipids, and 15 moreVitamin A, Methods, Vitamin E, Vitamin, Retinol, Retinoic Acid, Column chromatography, Analytical Biochemistry, Quntitative Thin Layer Chromatography, Silicon Dioxide, Esters, Biochemistry and cell biology, Silicic acid, Elution, and stereoisomerism
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... more
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.
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Research Interests: Developmental Biology, Biology, Membrane Proteins, Medicine, In Situ Hybridization, and 14 moreBiological Sciences, Female, Animals, RETINOIDS, Chickens, Time Factors, Retinoic Acid, Tretinoin, Quail, Embryos, Gene expression profiling, reverse transcriptase polymerase chain reaction, Chick embryo, and Medical and Health Sciences
We report here the development and rescue of the truncated hindbrain of retinoid-deprived quail embryos. The embryo is completely rescued by an injection of retinol into the egg; this confirms retinol, or a related retinoid, as a required... more
We report here the development and rescue of the truncated hindbrain of retinoid-deprived quail embryos. The embryo is completely rescued by an injection of retinol into the egg; this confirms retinol, or a related retinoid, as a required molecule in hindbrain development. Staging the retinoid replacement enabled us to determine that the 3-4 somite stage is the period when retinoids are required for normal development. Analysis of the development of the retinoid-deprived hindbrain phenotype through somitogenesis has revealed a pathway of retinoid action in early hindbrain regionalization. The hindbrain of the retinoid-deprived embryo is normal in size, during early somitogenesis, but has a respecified pattern of Krox-20 expression. From the earliest expression of Krox-20, at the 5 somite stage, the rhombomere 3 stripe fills the caudal third of the developing hindbrain to the level of the first somite. Morphologically only 2, instead of the normal 5, rhombomere bulges form. These 2 bulges express genes and, later, develop morphology characteristic of rhombomeres 1 and 2 and rhombomere 3. Posterior hindbrain specific genes, Hoxb-1, Fgf3, MafB, and the rhombomere 5 stripe of Krox-20 are never expressed in the head neuroepithelium of these embryos. From the initial formation of the neural plate, there is no evidence of rhombomere 4-7 specific characteristics. These results indicate the specification of the posterior hindbrain is lost and its cells participate in the formation of an enlarged anterior hindbrain. In our previous study, we reported the absence of the posterior hindbrain in retinoid-deprived quails (Maden, M., Gale, E., Kostetskii, I., Zile, M., 1996. Vitamin A-deficient quail embryos have half a hindbrain and other neural defects. Curr. Biol. 6, 417-426). Here, we show this phenotype to be the result of respecification of the hindbrain cells. This provides evidence for a region specific response to a single stimulus, retinol, which suggests a pre-rhombomeric regionalization of the hindbrain.
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We describe here how the early limb bud of the quail embryo develops in the absence of retinoids, including retinoic acid. Retinoid-deficient embryos develop to about stage 20/21, thus allowing patterns of early gene activity in the limb... more
We describe here how the early limb bud of the quail embryo develops in the absence of retinoids, including retinoic acid. Retinoid-deficient embryos develop to about stage 20/21, thus allowing patterns of early gene activity in the limb bud to be readily examined. Genes representing different aspects of limb polarity were analysed. Concerning the anteroposterior axis, Hoxb-8 was up-regulated and its border was shifted anteriorly whereas shh and the mesodermal expression of bmp-2 were down-regulated in the absence of retinoids. Concerning the apical ectodermal genes, fgf-4 was down-regulated whereas fgf-8 and the ectodermal domain of bmp-2 were unaffected. Genes involved in dorsoventral polarity were all disrupted. Wnt-7a, normally confined to the dorsal ectoderm, was ectopically expressed in the ventral ectoderm and the corresponding dorsal mesodermal gene Lmx-1 spread into the ventral mesoderm. En-1 was partially or completely absent from the ventral ectoderm. These dorsoventral patterns of expression resemble those seen in En-1 knockout mouse limb buds. Overall, the patterns of gene expression are also similar to the Japanese limbless mutant. These experiments demonstrate that the retinoid-deficient embryo is a valuable tool for dissecting pathways of gene activity in the limb bud and reveal for the first time a role for retinoic acid in the organisation of the dorsoventral axis.
Research Interests: Biology, Transcription Factors, Medicine, Gene expression, In Situ Hybridization, and 15 moreBone Morphogenetic Proteins, Biological Sciences, Animals, RETINOIDS, Proteins, Fibroblast Growth Factor, Body Patterning, Retinoic Acid, Limb Development, Embryos, Embryo Development, ovum, Sonic hedgehog, Medical and Health Sciences, and Fibroblast growth factors
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Research Interests: Developmental Biology, Transcription Factors, In Situ Hybridization, Signal Transduction, Biological Sciences, and 13 moreVitamin A, Cell Differentiation, Animals, Heart Development, Heart, RETINOIDS, Phenotype, Transcription Factor, Myocardium, Vitamin A deficiency, Embryos, DNA binding proteins, and Medical and Health Sciences
Research Interests: Developmental Biology, Biology, Morphogenesis, Medicine, Gene expression, and 15 moreBone Morphogenetic Proteins, Embryo, Biological Sciences, Humans, Mice, Chicken, Animals, Heart, Developmental, Epidermal Growth Factor, Body Patterning, Embryos, Chick embryo, Medical and Health Sciences, and Expression pattern
Research Interests: Developmental Biology, Transcription Factors, Apoptosis, Gene expression, In Situ Hybridization, and 15 moreBiological Sciences, Animals, Heart, Phenotype, Digestive System, Chimera, Retinoic Acid, Vitamin A deficiency, Tretinoin, Quail, Embryos, DNA binding proteins, endoderm, Chick embryo, and Medical and Health Sciences
Research Interests: Biology, Biological Sciences, Neural Crest, Animals, Hindbrain, and 12 moreCentral Nervous System, Retinoic Acid, Vitamin A deficiency, Tretinoin, Nervous System, Neural Tube Defects, Quail, Embryos, Neurite Outgrowth, Psychology and Cognitive Sciences, Medical and Health Sciences, and Expression pattern
Vitamin A requirement for early embryonic development is clearly evident in the gross cardiovascular and central nervous system abnormalities and an early death of the vitamin A-deficient quail embryo. This retinoid knockout model system... more
Vitamin A requirement for early embryonic development is clearly evident in the gross cardiovascular and central nervous system abnormalities and an early death of the vitamin A-deficient quail embryo. This retinoid knockout model system was used to examine the biological activity of various natural retinoids in early cardiovascular development. We demonstrate that all-trans-, 9-cis-, 4-oxo-, and didehydroretinoic acids, and didehydroretinol and all-trans-retinol induce and maintain normal cardiovascular development as well as induce expression of the retinoic acid receptor beta2 in the vitamin A-deficient quail embryo. The expression of RARbeta2 is at the same level and at the same sites where it is expressed in the normal embryo. Retinoids provided to the vitamin A-deficient embryo up to the 5-somite stage of development, but not later, completely rescue embryonic development, suggesting the 5-somite stage as a critical retinoid-sensitive time point during early avian embryogenesis. Retinoid receptors RARalpha, RARgamma, and RXRalpha are expressed in both the precardiac endoderm and mesoderm in the normal and the vitamin A-deficient quail embryo, while the expression of RXRgamma is restricted to precardiac endoderm. Vitamin A deficiency downregulates the expression of RARalpha and RARbeta. Our studies provide strong evidence for a narrow retinoid-requiring developmental window during early embryogenesis, in which the presence of bioactive retinoids and their receptors is essential for a subsequent normal embryonic development.
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Retinoids, and in particular retinoic acid (RA), are known to induce posterior fates in neural tissue. However, alterations in retinoid signalling dramatically affect anterior development. Previous reports have demonstrated a late role... more
Retinoids, and in particular retinoic acid (RA), are known to induce posterior fates in neural tissue. However, alterations in retinoid signalling dramatically affect anterior development. Previous reports have demonstrated a late role for retinoids in patterning craniofacial and forebrain structures,but an earlier role in anterior patterning is not well understood. We show that enzymes involved in synthesizing retinoids are expressed in the avian hypoblast and in tissues directly involved in head patterning, such as anterior definitive endoderm and prechordal mesendoderm. We found that in the vitamin A-deficient (VAD) quail model, which lacks biologically active RA from the first stages of development, anterior endodermal markers such as Bmp2,Bmp7, Hex and the Wnt antagonist crescent are affected during early gastrulation. Furthermore, prechordal mesendodermal and prospective ventral telencephalic markers are expanded posteriorly, Shhexpression in the axial mesoderm is reduced, and...
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Research Interests: Biology, Morphogenesis, Medicine, Hematopoiesis, Signal Transduction, and 15 moreEmbryo, Cell Differentiation, Animals, Blood, RETINOIDS, Clinical Sciences, Quail, Embryos, DNA binding proteins, Hemoglobins, Blood cells, Signaling pathway, Cardiovascular medicine and haematology, Paediatrics and reproductive medicine, and Embryo Culture
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Both Hensen's node, the organizer center in chick embryo, and exogenous retinoic acid are known to induce limb duplication when grafted or applied to the host chick limb bud. Retinoic acid is known to be present in the node and has... more
Both Hensen's node, the organizer center in chick embryo, and exogenous retinoic acid are known to induce limb duplication when grafted or applied to the host chick limb bud. Retinoic acid is known to be present in the node and has been proposed as the putative morphogen for ...
Research Interests: Developmental Biology, In Situ Hybridization, Biological Sciences, Cell and Tissue Transplantation, Animals, and 15 moreRETINOIDS, Proteins, High Pressure Liquid Chromatography, Retinoic Acid, Vitamin A deficiency, Tretinoin, Limb Development, Embryos, Biological Assay, Extremities, ovum, Sonic hedgehog, Chick embryo, Reporter gene, and Medical and Health Sciences
The influence of vitamin A depletion on tissue composition was studied in rats that were marginally vitamin A deficient, i.e. at their weight plateau stage. The total number of cells (DNA) was decreased in most organs as a result of... more
The influence of vitamin A depletion on tissue composition was studied in rats that were marginally vitamin A deficient, i.e. at their weight plateau stage. The total number of cells (DNA) was decreased in most organs as a result of vitamin A depletion. In thymus, spleen and the sublingual glands there was also a dramatic reduction in the number of cells per gram of tissue and in thymus and sublingual glands there was an increase in the protein to DNA ratio as a result of absence of dietary.vitamin A. We present the hypothesis that vitamin A stimulates growth by a direct role in cell replication in addition to or instead of stimulating the differentiation of epithelial and bone cells.