Vitamin A in Reproduction and Development

Clagett-Dame, Margaret; Knutson, Danielle

doi:10.3390/nu3040385

Cited by 439Retinoids in leukemia and cellular processesRetinal Development and DisordersBirth, Development, and Health

Vitamin A in Reproduction and Development

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Clagett-Dame, Margaret, Knutson, Danielle·2011·Nutrients

DOI 10.3390/nu3040385PMC PMC3257687

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Abstract

The requirement for vitamin A in reproduction was first recognized in the early 1900’s, and its importance in the eyes of developing embryos was realized shortly after. A greater understanding of the large number of developmental processes that require vitamin A emerged first from nutritional deficiency studies in rat embryos, and later from genetic studies in mice. It is now generally believed that all-trans retinoic acid (RA) is the form of vitamin A that supports both male and female reproduction as well as embryonic development. This conclusion is based on the ability to reverse most reproductive and developmental blocks found in vitamin A deficiency induced either by nutritional or genetic means with RA, and the ability to recapitulate the majority of embryonic defects in retinoic acid receptor compound null mutants. The activity of the catabolic CYP26 enzymes in determining what tissues have access to RA has emerged as a key regulatory mechanism, and helps to explain why exogenous RA can rescue many vitamin A deficiency defects. In severely vitamin A-deficient (VAD) female rats, reproduction fails prior to implantation, whereas in VAD pregnant rats given small amounts of carotene or supported on limiting quantities of RA early in organogenesis, embryos form but show a collection of defects called the vitamin A deficiency syndrome or late vitamin A deficiency. Vitamin A is also essential for the maintenance of the male genital tract and spermatogenesis. Recent studies show that vitamin A participates in a signaling mechanism to initiate meiosis in the female gonad during embryogenesis, and in the male gonad postnatally. Both nutritional and genetic approaches are being used to elucidate the vitamin A-dependent pathways upon which these processes depend.

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Vitamin A or retinol is essential for human survival at every point, from embryogenesis to adulthood.
“Vitamin A or retinol is essential for human survival at every point, from embryogenesis to adulthood ( 2,3 ).”
From Vitamin A and retinoid signaling: genomic and nongenomic effects (2013) · cites this paper as [3]
The Abstract and Section 3.4 describe vitamin A’s role in reproduction and embryonic development, while Section 1 (Background) calls it an essential micronutrient and describes its role in growth and tissue maintenance. The evidence discussed is largely from animal studies; these passages do not establish the stronger claim that vitamin A is essential for human survival at every point from embryogenesis to adulthood. (LLM, conf=0.84)
Experimental — accuracy not yet measured
Several studies show a connection between maternal vitamin A deficiency and diabetes mellitus in adulthood and gestational diabetes, and vitamin A deficiency affects fetal endocrine pancreas development.
“Moreover, several studies show a connection between maternal vitamin A deficiency and diabetes mellitus in adulthood and gestational diabetes. During pregnancy, as shown by several animal studies, vitamin A deficiency affects fetal development negatively, particularly in endocrine pancreas development, suggesting a dominant impact of this micronutrient in the diabetic pathogenesis [128,129].”
From Maternal Overnutrition and Fetal Programming: Long-Term Metabolic, Cognitive, and Epigenetic Consequences (2026) · cites this paper as [129]
Section 3.14 (Pancreas; page unavailable) reports that retinoic acid is required for early dorsal pancreas development in mice and that deficient signaling disrupts pancreatic specification. It does not establish an effect specifically on the fetal endocrine pancreas, and the passages do not report a connection between maternal vitamin A deficiency and adult or gestational diabetes. The section also notes that pancreatic defects were not observed as part of the vitamin A deficiency syndrome. (LLM, conf=0.86)
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Excess vitamin A has teratogenic effects; a vitamin A intake exceeding 10,000 UI at the beginning of the first trimester can lead to serious congenital malformations involving the central nervous system and cardiovascular system, causing miscarriage in the most serious cases.
“It is widely known that, conversely, excess vitamin A has teratogenic effects. A vitamin A intake exceeding 10,000 UI at the beginning of the first trimester can lead to serious congenital malformations involving the central nervous system and cardiovascular system, causing miscarriage in the most serious cases.”
From Maternal Overnutrition and Fetal Programming: Long-Term Metabolic, Cognitive, and Epigenetic Consequences (2026) · cites this paper as [129]
Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
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Vitamin A is a vital micronutrient during pregnancy for both the mother and the baby, playing a key role in vision, cell differentiation, eye health, bone formation, immune function, and embryonic development.
“Vitamin A is a vital micronutrient during pregnancy for both the mother and the baby. It plays a key role in vision, as it is a precursor of rhodopsin, a crucial pigment in retinal photoreceptor cells. It is also involved in cell differentiation, helps preserve eye health, and prevents xerophthalmia; its deficiency remains the leading cause of avoidable blindness worldwide.”
From Maternal Overnutrition and Fetal Programming: Long-Term Metabolic, Cognitive, and Epigenetic Consequences (2026) · cites this paper as [129]
The Female Reproduction section says maternal vitamin A status throughout pregnancy is critical to reproductive outcome, and the Eye Development section documents its role in embryonic eye development. The cited passages do not establish the printed sentence’s specific claims about rhodopsin, xerophthalmia, or vitamin A deficiency being the leading cause of avoidable blindness worldwide. The supplied paraphrase also adds immune function, which these passages do not support. (LLM, conf=0.86)
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Vitamin A deficiency is a major cause of anemia and influences hematopoiesis, iron metabolism, and immune function.
“Vitamin A deficiency is a major cause of anemia. Recent studies have shown that vitamin A supplementation during pregnancy increases hemoglobin levels. Although the exact mechanism linking serum retinol levels and anemia is not yet fully understood, it is clear that vitamin A influences hematopoiesis, iron metabolism, and immune function.”
From Maternal Overnutrition and Fetal Programming: Long-Term Metabolic, Cognitive, and Epigenetic Consequences (2026) · cites this paper as [129]
The passages in §§2.2 and 3.1 discuss reproductive outcomes and embryonic defects from vitamin A deficiency, not anemia. Searches for anemia, hemoglobin, hematopoiesis, iron metabolism, and immune function found no passage in our copy addressing the attributed claim. (LLM, conf=0.76)
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T<scp>HE</scp>R<scp>OLE OF</scp>V<scp>ITAMIN</scp>A<scp>IN</scp>M<scp>AMMALIAN</scp>R<scp>EPRODUCTION AND</scp>E<scp>MBRYONIC</scp>D<scp>EVELOPMENT</scp>
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Opposing RA and FGF signals control proximodistal vertebrate limb development through regulation of Meis genes.
Mercader, N., Leonardo, E., Piedra, M., Martı́nez-A, C., Ros, M. A., & Torres, M. (2000) · Development · doi:10.7892/boris.79628 · Cited by 339 · cited 1×
“RA has been proposed to play a role in patterning the developing limb by regulating the pattern of expression of genes such as Hand2 (activates SHH), Shh (patterns the anterior-to-posterior axis), and Meis1/2 (transcription factors that mark the proximal limb bud mesenchyme) [287,290–292].”
Background
From carrot to clinic: an overview of the retinoic acid signaling pathway
Theodosiou, M., Laudet, V., & Schubert, M. (2010) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-010-0268-z · Cited by 329 · cited 1× · see citing works
“mice; some have been found to be dispensable, while roles for others have been revealed when animals are fed a vitamin A-restricted diet [12,27,28].”
Background
Nephron number, hypertension, renal disease, and renal failure.
Hoy, W., Hughson, M., Bertram, J., Douglas-Denton, R. N., & Amann, K. (2005) · Journal of the American Society of Nephrology · doi:10.1681/asn.2005020172 · Cited by 320 · cited 1× · see citing works
“In kidney, the number of embryonic branching events determines the final number of nephrons an individual will have for life, and it has been proposed that suboptimal nephron number at birth increases susceptibility to acquired renal disease and essential hypertension later in life [243–246].”
Background
A newborn lethal defect due to inactivation of retinaldehyde dehydrogenase type 3 is prevented by maternal retinoic acid treatment
Dupé, V., Matt, N., Garnier, J., Chambon, P., Mark, M. P., & Ghyselinck, N. B. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2336223100 · Cited by 319 · cited 2× · see citing works
“RA acting through the RAR is also necessary for the morphogenesis of other components of the respiratory tract including partitioning of the primitive foregut into oesophagus and trachea, and for the opening between the nasal and oropharyngeal cavities [67,131,209,256,258,261].”
Background
Regulation of Retinoic Acid Distribution Is Required for Proximodistal Patterning and Outgrowth of the Developing Mouse Limb
Yashiro, K., Zhao, X., Uehara, M., Yamashita, K., Nishijima, M., Nishino, J., Saijoh, Y., Sakai, Y., & Hamada, H. (2004) · Developmental Cell · doi:10.1016/s1534-5807(04)00062-0 · Cited by 316 · cited 2× · see citing works
“These studies show that controlled exclusion of RA from the limb bud is essential for proper limb morphology [142].”
Background
Retinoic acid signaling is required for a critical early step in zebrafish pancreatic development
Stafford, D., & Prince, V. E. (2002) · Current Biology · doi:10.1016/s0960-9822(02)00929-6 · Cited by 309 · cited 1× · see citing works
“The effects of RA deficiency on pancreatic lineages appear to be due to the loss of pancreatic field specification within the endoderm [274].”
Background
Postnatal treatment with retinoic acid increases the number of pulmonary alveoli in rats.
Massaro, G., & Massaro, D. (1996) · American Journal of Physiology · doi:10.1152/ajplung.1996.270.2.l305 · Cited by 309 · cited 1× · see citing works
“reports that exogenous RA can stimulate alveoli formation in immature rat and mouse lung [264–269].”
Background
Opposing FGF and retinoid pathways: a signalling switch that controls differentiation and patterning onset in the extending vertebrate body axis
del Corral, R. D., & Storey, K. G. (2004) · BioEssays · doi:10.1002/bies.20080 · Cited by 295 · see citing works
Dorsal pancreas agenesis in retinoic acid-deficient Raldh2 mutant mice.
Martín, M., Gallego-Llamas, J., Ribes, V., Kedinger, M., Niederreither, K., Chambon, P., Dollé, P., & Gradwohl, G. (2005) · Developmental Biology · doi:10.1016/j.ydbio.2005.05.035 · Cited by 295 · cited 5× · see citing works
“null mutant mice, a requirement for RA in pancreatic development has been proposed based on studies in RALDH null mutant mice [271,272] and in several other organisms in which retinoid signaling is deficient or inhibited, including Xenopus, zebrafish, chick, and quail [273–276].”
BackgroundInfluential
Apoptotic extinction of germ cells in testes of Cyp26b1 knockout mice.
Maclean, G., Li, H., Metzger, D., Chambon, P., & Petkovich, M. (2007) · Endocrinology · doi:10.1210/en.2007-0492 · Cited by 291 · cited 2× · see citing works
“5, and this is followed by apoptosis [73].”
Background
Stem cells, signals and vertebrate body axis extension
Wilson, V., Olivera-Martinez, I., & Storey, K. G. (2009) · Development · doi:10.1242/dev.021246 · Cited by 290 · cited 1× · see citing works
“comprises the caudal end of the node and the rostral end of the primitive streak [186].”
Background
Teratology of Retinoids
Collins, M. D., & Mao, G. E. (1999) · The Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev.pharmtox.39.1.399 · Cited by 290 · cited 1× · see citing works
“However, too much RA at critical stages can result in embryo lethality or malformation [117–120].”
Background
Vitamin A controls epithelial/mesenchymal interactions through Ret expression
Batourina, E., Gim, S., Bello, N. A., Shy, M., Clagett‐Dame, M., Srinivas, S., Costantini, F. D., & Mendelsohn, C. L. (2001) · Nature Genetics · doi:10.1038/83792 · Cited by 288 · cited 3× · see citing works
“mutants rescues renal development, restoring ureteric bud growth and stromal cell patterning [237].”
BackgroundSelf-citation
Signaling Gradients during Paraxial Mesoderm DevelopmentPreprint
Aulehla, A., & Pourquie, O. (2009) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a000869 · Cited by 277 · cited 2× · see citing works
“RA plays a role in the initiation of differentiation of the anterior region of the presomitic mesoderm from which the new somites originate [217].”
Background
Signaling Pathways Controlling Second Heart Field Development
Rochais, F., Mesbah, K., & Kelly, R. (2009) · Circulation Research · doi:10.1161/circresaha.109.194464 · Cited by 276 · cited 1× · see citing works
“reviews [229,232,234].”
The key role of vitamin A in spermatogenesis.
Hogarth, C., & Griswold, M. (2010) · Journal of Clinical Investigation · doi:10.1172/jci41303 · Cited by 263 · cited 2× · see citing works
“Recent work supports the conclusion that the vitamin A metabolite, RA, is needed both for adult male spermatogonial differentiation (transition to A1) and the entrance into meiosis [45–47].”
BackgroundResult
Aortic-arch and cardiac anomalies in the offspring of vitamin A deficient rats.
Wilson, J. G., & Warkany, J. (1949) · American Journal of Anatomy · doi:10.1002/aja.1000850106 · Cited by 261 · cited 1× · see citing works
“Cardiac and aortic arch defects were observed as a part of the early vitamin A deficiency syndrome in rat embryos [93,94] and in RAR compound null mutant mouse embryos [98,102].”
Background
Expression of Stimulated by Retinoic Acid Gene 8 (Stra8) in Spermatogenic Cells Induced by Retinoic Acid: An In Vivo Study in Vitamin A-Sufficient Postnatal Murine Testes1
Zhou, Q., Nie, R., Li, Y., Friel, P., Mitchell, D., Hess, R., Small, C., & Griswold, M. (2008) · Biology of Reproduction · doi:10.1095/biolreprod.107.066795 · Cited by 260 · cited 1× · see citing works
“testis by postnatal day 6 [84] and spermatogenesis begins shortly thereafter [85].”
Background
Retinoic acid metabolism and signaling pathways in the adult and developing mouse testis.
Vernet, N., Dennefeld, C., Rochette-Egly, C., Oulad-Abdelghani, M., Chambon, P., Ghyselinck, N., & Mark, M. (2006) · Endocrinology · doi:10.1210/en.2005-0953 · Cited by 259 · cited 4× · see citing works
“Within the normal tubule, the Sertoli cell is believed to generate RA by the action of Raldh1 [49,51,52], and possibly Raldh2 [50].”
BackgroundInfluential
Retinoic acid-dependent eye morphogenesis is orchestrated by neural crest cells
Matt, N., Dupé, V., Garnier, J., Dennefeld, C., Chambon, P., Mark, M. P., & Ghyselinck, N. B. (2005) · Development · doi:10.1242/dev.02031 · Cited by 256 · cited 3× · see citing works
“A number of eye defects in RALDH3 and RALDH1/3 compound mutants [134,135,178] are also similar to those observed in late VAD rat embryos.”
Background
Endogenous distribution of retinoids during normal development and teratogenesis in the mouse embryo
Horton, C., & Maden, M. (1995) · Developmental Dynamics · doi:10.1002/aja.1002020310 · Cited by 256 · see citing works
Mild vitamin A deficiency leads to inborn nephron deficit in the rat.
Lelièvre-Pégorier, M., Vilar, J., Ferrier, M., Moreau, E., Freund, N., Gilbert, T., & Merlet-Bénichou, C. (1998) · Kidney International · doi:10.1046/j.1523-1755.1998.00151.x · Cited by 250 · see citing works
Identification of the human cytochrome P450, P450RAI-2, which is predominantly expressed in the adult cerebellum and is responsible for all- <i>trans</i> -retinoic acid metabolism
White, J. A., Ramshaw, H., Taimi, M., Stangle, W., Zhang, A., Everingham, S., Creighton, S., Tam, S.-P., Jones, G., & Petkovich, M. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.120161397 · Cited by 248 · cited 1× · see citing works
“family (A1, B1 and C1) [17–23].”
FGF9 suppresses meiosis and promotes male germ cell fate in mice.
Bowles, J., Feng, C., Spiller, C. M., Davidson, T.-L., Jackson, A., & Koopman, P. (2010) · Developmental Cell · doi:10.1016/j.devcel.2010.08.010 · Cited by 247 · cited 1× · see citing works
“(Adapted from [77,78]).”
Differential expression of retinoic acid-synthesizing (RALDH) enzymes during fetal development and organ differentiation in the mouse
Niederreither, K., Fraulob, V., Garnier, J.-M., Chambon, P., & Dollé, P. (2002) · Mechanisms of Development · doi:10.1016/s0925-4773(01)00561-5 · Cited by 246 · cited 1× · see citing works
“In the embryonic kidney, Raldh2 is localized in stromal mesenchyme of the outer cortex and Raldh3 is expressed in the ureteric bud [130,237,238].”
Background
Cyp26 enzymes generate the retinoic acid response pattern necessary for hindbrain development
Hernandez, R. E., Putzke, A. P., Myers, J. P., Margaretha, L., & Moens, C. B. (2007) · Development · doi:10.1242/dev.02706 · Cited by 245 · cited 9× · see citing works
“Interestingly, in Cyp26 morpholino studies in zebrafish, restriction of the RA-responsive gene, Vhnff1, is determined by the posterior limit of Cyp26C1 at the r4/r5 boundary, a function that can be compensated for by CYP26B1 [173].”
BackgroundInfluential
Dynamic and combinatorial control of gene expression by nuclear retinoic acid receptors (RARs)
Rochette‐Egly, C., & Germain, P. (2009) · Nuclear Receptor Signaling · doi:10.1621/nrs.07005 · Cited by 244 · cited 1× · see citing works
“The nuclear RARs act as ligand-activated transcription factors to regulate gene transcription in a cell-type and tissue-specific manner [30].”
Background
Medium-chain and short-chain dehydrogenases/reductases in retinoid metabolism
Parés, X., Farrés, J., Kedishvili, N., & Duester, G. (2008) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-008-8591-3 · Cited by 242 · see citing works
Retinoid activation of retinoic acid receptor but not retinoid X receptor is sufficient to rescue lethal defect in retinoic acid synthesis
Mic, F., Molotkov, A., Benbrook, D., & Duester, G. (2003) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.1231422100 · Cited by 242 · cited 1× · see citing works
“However, work from the Duester group indicates that ligand binding to the RAR is sufficient to transduce the signal, as a RAR- but not a RXR- selective ligand is able to rescue the developmental defects in RALDH2 null mutant embryos [108].”
Background
Role of the retinoic acid receptor beta (RARbeta) during mouse development.
Ghyselinck, N., Dupé, V., Dierich, A., Messaddeq, N., Garnier, J.-M., Rochette-Egly, C., Chambon, P., & Mark, M. (1997) · International Journal of Developmental Biology · doi:10.1387/ijdb.9240560 · Cited by 240 · cited 7× · see citing works
“number of RAR mutants show both cervical anteriorizations and posteriorization at the cervical thoracic junction [97,209].”
BackgroundInfluential
Vitamin A and carotene
Moore, T. S., II (1930) · Biochemical Journal · doi:10.1042/bj0240692 · Cited by 233 · cited 1× · see citing works
“This problem was solved when Moore fed carotenoids to vitamin A-deficient (VAD) rats in amounts that enabled the animals to resume normal growth, and showed that only the ―colorless‖ form of vitamin A was found in the livers collected from these animals [5].”
Background
Teratogenic activity of retinoic acid.
Kochhar, D. (2009) · Acta pathologica et microbiologica Scandinavica · doi:10.1111/j.1699-0463.1967.tb01308.x · Cited by 231 · cited 1× · see citing works
“However, too much RA at critical stages can result in embryo lethality or malformation [117–120].”
Background
RXR gamma null mice are apparently normal and compound RXR alpha +/-/RXR beta -/-/RXR gamma -/- mutant mice are viable.
Krężel, W., Dupé, V., Mark, M., Dierich, A., Kastner, P., & Chambon, P. (1996) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.93.17.9010 · Cited by 231 · cited 1× · see citing works
“RAR/RXR heterodimers form the functional unit that transduces the RA signal, with one genomic copy of the Rxrα sufficient to support RXR function in embryogenesis [105].”
Background
Targeted Disruption of Aldh1a1 (Raldh1) Provides Evidence for a Complex Mechanism of Retinoic Acid Synthesis in the Developing Retina
Fan, X., Molotkov, A., Manabe, S.-I., Donmoyer, C. M., Deltour, L., Foglio, M. H., Cuenca, A. E., Blaner, W. S., Lipton, S. A., & Duester, G. (2003) · Molecular and Cellular Biology · doi:10.1128/mcb.23.13.4637-4648.2003 · Cited by 230 · cited 1× · see citing works
“Deletion of RALDH2 is lethal early in development, whereas RALDH3 null mutants die at birth [131], and RALDH1 mutants are viable [133].”
Background
Retinoic acid and pattern formation in vertebrates.
Conlon, R. A. (1995) · Trends in Genetics · doi:10.1016/s0168-9525(00)89089-7 · Cited by 225 · cited 1× · see citing works
“However, too much RA at critical stages can result in embryo lethality or malformation [117–120].”
Background
Mice bearing deletions of retinoic acid receptors demonstrate reduced lung elastin and alveolar numbers.
McGowan, S., Jackson, S. K., Jenkins-Moore, M., Dai, H.-H., Chambon, P., & Snyder, J. M. (2000) · American Journal of Respiratory Cell and Molecular Biology · doi:10.1165/ajrcmb.23.2.3904 · Cited by 216 · cited 1× · see citing works
“reports that exogenous RA can stimulate alveoli formation in immature rat and mouse lung [264–269].”
Background
Retinoic acid generated by Raldh2 in mesoderm is required for mouse dorsal endodermal pancreas development
Molotkov, A., Molotkova, N., & Duester, G. (2005) · Developmental Dynamics · doi:10.1002/dvdy.20256 · Cited by 211 · cited 5× · see citing works
“null mutant mice, a requirement for RA in pancreatic development has been proposed based on studies in RALDH null mutant mice [271,272] and in several other organisms in which retinoid signaling is deficient or inhibited, including Xenopus, zebrafish, chick, and quail [273–276].”
BackgroundInfluential
A novel human cytochrome P450, CYP26C1, involved in metabolism of 9-cis and all-trans isomers of retinoic acid
Taimi, M., Helvig, C., Wisniewski, J., Ramshaw, H., White, J., Amad, M., Korczak, B., & Petkovich, M. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m308337200 · Cited by 211 · cited 1× · see citing works
“family (A1, B1 and C1) [17–23].”
Retinoic acid guides eye morphogenetic movements via paracrine signaling but is unnecessary for retinal dorsoventral patterning
Molotkov, A., Molotkova, N., & Duester, G. (2006) · Development · doi:10.1242/dev.02328 · Cited by 210 · cited 2× · see citing works
“A number of eye defects in RALDH3 and RALDH1/3 compound mutants [134,135,178] are also similar to those observed in late VAD rat embryos.”
Background
Early regionalization of somitic mesoderm as studied by the development of axial skeleton of the chick embryo.
Kieny, M., Mauger, A., & Sengel, P. (1972) · Developmental Biology · doi:10.1016/0012-1606(72)90133-9 · Cited by 209 · see citing works
Malformations in the genito-urinary tract induced by maternal vitamin A deficiency in the rat.
Wilson, J. G., & Warkany, J. (1948) · American Journal of Anatomy · doi:10.1097/00006254-194812000-00013 · Cited by 205 · cited 2×
“ureteric openings and other genitourinary tract defects have been reported in VAD rat fetuses [67,91].”
Background
PIGS BORN WITHOUT EYE BALLS
Hale, F. (1933) · Springer eBooks · doi:10.1007/978-94-011-6621-8_21 · Cited by 199 · cited 2× · see citing works
“Recognition of the importance of vitamin A in eye development first came from the experiments of Hale in which piglets from deficient mothers were born blind [86,87].”
Background
Retinol-induced stage synchronization in seminiferous tubules of the rat.
Morales, C., & Griswold, M. (1987) · Endocrinology · doi:10.1210/endo-121-1-432 · Cited by 194 · cited 2× · see citing works
“In vitamin A deficiency, the transition from A to A1 spermatogonia is blocked [42–44].”
Background
Retinoid signalling and hindbrain patterning
Gavalas, A., & Krumlauf, R. K. (2000) · Current Opinion in Genetics & Development · doi:10.1016/s0959-437x(00)00100-3 · Cited by 193 · cited 1× · see citing works
“the diverse range of nerves and craniofacial structures essential to hindbrain function [161].”
Background
Differences in testis injury and repair after vitamin A-deficiency, vitamin E-deficiency, and inanition†
Mason, K. E. (1933) · doi:10.1002/aja.1000520202 · Cited by 190 · cited 1×
“Early work in the laboratories of Wolbach and Howe as well as Mason showed that in vitamin A deficiency, the epithelia of the epididymis, prostate, and seminal vesicle is replaced with stratified squamous keratinizing epithelium, and spermatogenesis ceases [2,38].”
Result
Retinoic acid treatment partially rescues failed septation in rats and in mice.
Massaro, G., & Massaro, D. (2000) · American Journal of Physiology - Lung cellular and Molecular Physiology · doi:10.1152/ajplung.2000.278.5.l955 · Cited by 186 · cited 1× · see citing works
“reports that exogenous RA can stimulate alveoli formation in immature rat and mouse lung [264–269].”
Background
Congenital malformations induced in rats by maternal vitamin A deficiency; defects of the eye.
Warkany, J., & Schraffenberger, E. (1946) · A M A Archives of Ophthalmology · doi:10.1001/archopht.1946.00890200155008 · Cited by 184 · see citing works
Shifting boundaries of retinoic acid activity control hindbrain segmental gene expression
Sîrbu, I. O., Gresh, L., Barra, J., & Duester, G. (2005) · Development · doi:10.1242/dev.01845 · Cited by 184 · cited 1× · see citing works
“developing hindbrain all include an important role for CYP26 family members in regulating the formation of waves or pulses of RA in this dynamic process [23,144,172,173].”
Background
Retinoic Acid Synthesis in Mouse Embryos during Gastrulation and Craniofacial Development Linked to Class IV Alcohol Dehydrogenase Gene Expression (*)
Ang, H., Deltour, L., Hayamizu, T. F., Žgombic-Knight, M., & Duester, G. (1996) · Journal of Biological Chemistry · doi:10.1074/jbc.271.16.9526 · Cited by 183 · cited 1× · see citing works
“Adh 1, 3 and 4 enzyme family members are also expressed in developing embryos [126,127], however, mutation does not result in embryo lethality [128,129].”
Background
Induction of normal cardiovascular development in the vitamin A-deprived quail embryo by natural retinoids.
Dersch, H., & Zile, M. (1993) · Developmental Biology · doi:10.1006/dbio.1993.1318 · Cited by 183 · cited 2× · see citing works
“When severe VAD is imposed in quail, the initiation of heart morphogenesis is disrupted [88,228,229].”
Background
Vitamin A deficiency results in the dose-dependent acquisition of anterior character and shortening of the caudal hindbrain of the rat embryo.
White, J. C., Highland, M., Kaiser, M., & Clagett-Dame, M. (2000) · Developmental Biology · doi:10.1006/dbio.2000.9635 · Cited by 182 · cited 4× · see citing works
“VAD rat embryos generated by severely restricting the amount of RA fed to deficient mothers at the beginning of pregnancy results in a loss of posterior rhombomere segmentation, with a significant shortening of the hindbrain [65].”
BackgroundInfluentialSelf-citation
Non-cell-autonomous retinoid signaling is crucial for renal development
Rosselot, C., Spraggon, L., Chia, I. V., Batourina, E., Riccio, P., Lu, B., Niederreither, K., Dollé, P., Duester, G., Chambon, P., et al. (2010) · Development · doi:10.1242/dev.040287 · Cited by 181 · cited 1× · see citing works
“Recent work shows that RA generated by RALDH2 in stromal mesenchyme acts in paracrine fashion to activate RA-receptor signaling and Ret expression in ureteric bud cells [242].”
Background
Retinoic Acid Promotes Limb Induction through Effects on Body Axis Extension but is Unnecessary for Limb Patterning
Zhao, X.-L., Sirbu, I. O., Mic, F., Molotkova, N., Molotkov, A., Kumar, S., & Duester, G. (2009) · Current Biology · doi:10.1016/j.cub.2009.04.059 · Cited by 178 · cited 3× · see citing works
“Raldh2 is largely responsible for RA synthesis in the mesonephros, with some contribution from Raldh3 in the region of the mesonephric duct [71,80].”
Background
Role of all-trans retinoic acid in neurite outgrowth and axonal elongation.
Clagett-Dame, M., McNeill, E., & Muley, P. D. (2006) · Journal of Neurobiology · doi:10.1002/neu.20241 · Cited by 178 · cited 2× · see citing works
“RA is also linked to the promotion of neurite outgrowth [157,162].”
BackgroundSelf-citation
Retinoic acid signaling is essential for pancreas development and promotes endocrine at the expense of exocrine cell differentiation in Xenopus
Chen, Y., Pan, F. C., Brandes, N., Afelik, S., Sölter, M., & Pieler, T. (2004) · Developmental Biology · doi:10.1016/j.ydbio.2004.03.030 · Cited by 172 · cited 2× · see citing works
“Both defects in RA signaling and RA treatment have been shown to affect the expression of PDX-1 [271,272,275,278] an essential regulator of early pancreas development required for the”
Background
Retinoic-acid signalling in node ectoderm and posterior neural plate directs left–right patterning of somitic mesoderm
Sirbu, I. O., & Duester, G. (2006) · Nature Cell Biology · doi:10.1038/ncb1374 · Cited by 171 · cited 2× · see citing works
“In RALDH2 null mutants, the expression of Fgf8 mRNA in the primitive ectoderm (epiblast) is shifted anteriorly such that it enters the node ectoderm and neuroectoderm, and somite development is abnormal [170].”
Background
The Relation of Vitamin a to Anophthalmos in Pigs
Hale, F. (1935) · American Journal of Ophthalmology · doi:10.1016/s0002-9394(35)90563-3 · Cited by 169 · cited 2× · see citing works
“Recognition of the importance of vitamin A in eye development first came from the experiments of Hale in which piglets from deficient mothers were born blind [86,87].”
Background
A retinoic acid synthesizing enzyme in ventral retina and telencephalon of the embryonic mouse.
Li, H., Wagner, E., McCaffery, P., Smith, D., Andreadis, A., & Dräger, U. C. (2000) · Mechanisms of Development · doi:10.1016/s0925-4773(00)00352-x · Cited by 167 · cited 1× · see citing works
“5 [132,148,203], after which Raldh3 (also called V1 activity) is expressed in the ventral neural retina and pigmented neuroepithelium [134,204–206] and Raldh1 (also called ADH-2) is expressed in the dorsal retina from E9.”
Background
Regulation and perturbation of testicular functions by vitamin A.
Livera, G., Rouiller-Fabre, V., Pairault, C., Levacher, C., & Habert, R. (2002) · Reproduction · doi:10.1530/rep.0.1240173 · Cited by 166 · cited 3× · see citing works
“Within the normal tubule, the Sertoli cell is believed to generate RA by the action of Raldh1 [49,51,52], and possibly Raldh2 [50].”
Background
Retinoic acid is required for the initiation of outgrowth in the chick limb bud.
Stratford, T., Horton, C., & Maden, M. (1996) · Current Biology · doi:10.1016/s0960-9822(02)70679-9 · Cited by 166 · cited 1× · see citing works
“Inhibitors of RA synthesis and vitamin A deficiency inhibit limb outgrowth in the quail [285,286].”
Background
Spermatogenic response to vitamin A in vitamin A deficient rats.
Huang, H.-F.-S., & Hembree, W. (1979) · Biology of Reproduction · doi:10.1095/biolreprod21.4.891 · Cited by 165 · cited 1×
“Later work showed that in the VAD rat testes, undifferentiated spermatogonia, Sertoli cells and a small number of preleptotene spermatocytes remain [39–41], whereas in the mouse,”
Background
CYP26A1 and CYP26C1 cooperatively regulate anterior–posterior patterning of the developing brain and the production of migratory cranial neural crest cells in the mouse
Uehara, M., Yashiro, K., Mamiya, S., Nishino, J., Chambon, P., Dollé, P., & Sakai, Y. (2006) · Developmental Biology · doi:10.1016/j.ydbio.2006.09.045 · Cited by 164 · cited 7× · see citing works
“This is followed by the later expression of Cyp26A1 in r2 and Cyp26C1 in r2 and r4 [18,21,139,144].”
BackgroundInfluential
Opposing effects of retinoic acid and FGF9 on Nanos2 expression and meiotic entry of mouse germ cells
Barrios, F., Filipponi, D., Pellegrini, M., Paronetto, M., Siena, S. D., Geremia, R., Rossi, P., Felici, M. D., Jannini, E., & Dolci, S. (2010) · Journal of Cell Science · doi:10.1242/jcs.057968 · Cited by 163 · cited 1× · see citing works
“(Adapted from [77,78]).”
Vertebrate limb development: moving from classical morphogen gradients to an integrated 4-dimensional patterning system.Preprint
Benazet, J.-D., & Zeller, R. (2009) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a001339 · Cited by 163 · cited 1× · see citing works
“RA has been proposed to play a role in patterning the developing limb by regulating the pattern of expression of genes such as Hand2 (activates SHH), Shh (patterns the anterior-to-posterior axis), and Meis1/2 (transcription factors that mark the proximal limb bud mesenchyme) [287,290–292].”
Background
RALDH3, a retinaldehyde dehydrogenase that generates retinoic acid, is expressed in the ventral retina, otic vesicle and olfactory pit during mouse development
Mic, F. A., Molotkov, A., Fan, X., Cuenca, A. E., & Duester, G. (2000) · Mechanisms of Development · doi:10.1016/s0925-4773(00)00434-2 · Cited by 163 · cited 1× · see citing works
“5 [132,148,203], after which Raldh3 (also called V1 activity) is expressed in the ventral neural retina and pigmented neuroepithelium [134,204–206] and Raldh1 (also called ADH-2) is expressed in the dorsal retina from E9.”
Background
Medium- and short-chain dehydrogenase/reductase gene and protein families
Eklund, H., & Ramaswamy, S. (2008) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-008-8589-x · Cited by 158 · cited 1×
“The first and rate-limiting step in the production of RA from retinol results from the action of cytosolic alcohol dehydrogenases (ADH) and microsomal retinol dehydrogenases (RDH) yielding all-trans retinaldehyde [13].”
Background
Distal ureter morphogenesis depends on epithelial cell remodeling mediated by vitamin A and Ret
Batourina, E., Choi, C., Paragas, N., Bello, N., Hensle, T., Costantini, F., Schuchardt, A., Bacallao, R., & Mendelsohn, C. (2002) · Nature Genetics · doi:10.1038/ng952 · Cited by 157 · see citing works
Retinoic acid regulates morphogenesis and patterning of posterior foregut derivatives
Wang, Z., Dollé, P., Cardoso, W. V., & Niederreither, K. (2006) · Developmental Biology · doi:10.1016/j.ydbio.2006.05.019 · Cited by 156 · cited 2× · see citing works
“RA acting through the RAR is also necessary for the morphogenesis of other components of the respiratory tract including partitioning of the primitive foregut into oesophagus and trachea, and for the opening between the nasal and oropharyngeal cavities [67,131,209,256,258,261].”
Background
Cyp26C1 encodes a novel retinoic acid-metabolizing enzyme expressed in the hindbrain, inner ear, first branchial arch and tooth buds during murine development.
Tahayato, A., Dollé, P., & Petkovich, M. (2003) · Gene Expression Patterns · doi:10.1016/s1567-133x(03)00066-8 · Cited by 156 · cited 1× · see citing works
“This is followed by the later expression of Cyp26A1 in r2 and Cyp26C1 in r2 and r4 [18,21,139,144].”
Background
Developmental roles of the retinoic acid receptors.
Lohnes, D., Mark, M., Mendelsohn, C., Dollé, P., Décimo, D., Lemeur, M., Dierich, A., Gorry, P., & Chambon, P. (1995) · Journal of Steroid Biochemistry and Molecular Biology · doi:10.1016/0960-0760(95)00094-g · Cited by 153 · cited 1× · see citing works
“importance of the RAR in mediating the actions of RA in developing embryos [99,101,102].”
Background
Developmental expression of retinoic acid receptors (RARs)
Dollé, P. (2009) · Nuclear Receptor Signaling · doi:10.1621/nrs.07006 · Cited by 152 · cited 1× · see citing works
“The Rars are widely expressed in development [100].”
Background
RALDH-independent generation of retinoic acid during vertebrate embryogenesis by CYP1B1
Chambers, D., Wilson, L. J., Maden, M., & Lumsden, A. (2007) · Development · doi:10.1242/dev.02815 · Cited by 152 · cited 2× · see citing works
“Cyp1B1 can also generate RA and is expressed at known sites of RALDH-independent retinoid signaling [16], however, null mutant mice for this gene are viable [137].”
Background
Stimulation of retinoic acid production and growth by ubiquitously expressed alcohol dehydrogenase Adh3
Molotkov, A., Fan, X., Deltour, L., Foglio, M. H., Martras, S., Farrés, J., Parés, X., & Duester, G. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.082093299 · Cited by 151 · cited 2× · see citing works
“postnatal lethality if maintained for two generations on a VAD diet [129].”
Background
Retinoic acid regulates endothelial cell proliferation during vasculogenesis
Lai, L., Bohnsack, B. L., Niederreither, K., & Hirschi, K. K. (2003) · Development · doi:10.1242/dev.00887 · Cited by 150 · cited 1× · see citing works
“Raldh2 in the embryo, along with expression in the visceral endoderm (extraembryonic) is required for vascular development in both the embryo proper, as well as the yolk sac [150–152].”
Background
Sex-specific timing of meiotic initiation is regulated by Cyp26b1 independent of retinoic acid signalling
Kumar, S., Chatzi, C., Brade, T., Cunningham, T. J., Zhao, X.-L., & Duester, G. (2011) · Nature Communications · doi:10.1038/ncomms1136 · Cited by 149 · cited 3× · see citing works
“However, a recent report shows that female RALDH2 and RALDH2/3 knockout gonads express Stra8 and undergo meiosis in the absence of detectable RA activity as assessed using a β2-RARE-lacZ (RARE-lacZ) reporter [74].”
BackgroundMethod
The role of CYP26 enzymes in defining appropriate retinoic acid exposure during embryogenesis.
Pennimpede, T., Cameron, D., Maclean, G., Li, H., Abu-Abed, S., & Petkovich, M. (2010) · Birth defects research. Clinical and molecular teratology · doi:10.1002/bdra.20709 · Cited by 147 · cited 3× · see citing works
“The rhombomere-specific expression pattern of the Cyp26 mRNAs led to the proposal that boundaries of RA activity are created by their expression [23,141,171] (Figure 4B).”
Background
Retinoic acid in the formation of the dorsoventral retina and its central projections.
Wagner, E., McCaffery, P., & Dräger, U. C. (2000) · Developmental Biology · doi:10.1006/dbio.2000.9719 · Cited by 146 · cited 1× · see citing works
“5 [132,148,203], after which Raldh3 (also called V1 activity) is expressed in the ventral neural retina and pigmented neuroepithelium [134,204–206] and Raldh1 (also called ADH-2) is expressed in the dorsal retina from E9.”
Background
Defects in embryonic hindbrain development and fetal resorption resulting from vitamin A deficiency in the rat are prevented by feeding pharmacological levels of all-trans-retinoic acid.
White, J. C., Shankar, V., Highland, M., Epstein, M., DeLuca, H., & Clagett-Dame, M. (1998) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.95.23.13459 · Cited by 146 · cited 2× · see citing works
“Nervous system, cardiovascular, and axial patterning defects result from early deficiency [63–66,96], whereas a less well-developed nasal region,”
BackgroundSelf-citation
Retinoic acid and hindbrain patterning
Glover, J. C., Renaud, J., & Rijli, F. M. (2006) · Journal of Neurobiology · doi:10.1002/neu.20272 · Cited by 145 · cited 1× · see citing works
“One of the best-studied functions of RA is in the developing hindbrain where it contributes to the anteroposterior patterning of the neural plate [159].”
Background
A retinoic acid-dependent network in the foregut controls formation of the mouse lung primordium.
Chen, F., Cao, Y.-X., Qian, J., Shao, F., Niederreither, K., & Cardoso, W. (2010) · Journal of Clinical Investigation · doi:10.1172/jci40253 · Cited by 142 · cited 2× · see citing works
“of Tgfβ signaling [262].”
Pathways of vitamin A delivery to the embryo: insights from a new tunable model of embryonic vitamin A deficiency.
Quadro, L., Hamberger, L., Gottesman, M., Wang, F., Colantuoni, V., Blaner, W., & Mendelsohn, C. (2005) · Endocrinology · doi:10.1210/en.2005-0158 · Cited by 142 · cited 6× · see citing works
“Retinol-binding protein (RBP or RBP4) carries the majority of retinol in the circulation [25], and a membrane receptor, STRA6, binds to RBP to enable efficient retinol uptake by a number of cells [26].”
BackgroundInfluential
Retinoid receptor signaling in postmitotic motor neurons regulates rostrocaudal positional identity and axonal projection pattern.
Sockanathan, S., Perlmann, T., & Jessell, T. (2003) · Neuron · doi:10.1016/s0896-6273(03)00532-4 · Cited by 142 · cited 1× · see citing works
“RA generated from within the spinal cord is required for the differentiation of a subset of lateral motor column (LMC) neurons that extend axons into the limb [192,193].”
Background
The control of morphogen signalling: Regulation of the synthesis and catabolism of retinoic acid in the developing embryo
Reijntjes, S., Blentic, A., Gale, E. A., & Maden, M. (2005) · Developmental Biology · doi:10.1016/j.ydbio.2005.06.019 · Cited by 137 · cited 1× · see citing works
“Interestingly, both the levels and domains of Cyp26 gene expression in the developing embryo are affected by retinoid status, whereas the Raldhs are unaffected [121].”
Background
Retinal dehydrogenase-2 is inhibited by compounds that induce congenital diaphragmatic hernias in rodents.
Mey, J., Babiuk, R. P., Clugston, R. D., Zhang, W., & Greer, J. (2003) · American Journal of Pathology · doi:10.1016/s0002-9440(10)63861-8 · Cited by 137 · cited 1×
“Similar defects in PPF development are seen in rat embryos treated with nitrofen and several other CDH-inducing teratogens that interfere with the synthesis of RA and RA signaling in vivo [253,254].”
Background
Congenital Malformations Induced in Rats by Maternal Vitamin A Deficiency II. Effect of Varying the Preparatory Diet Upon the Yield of Abnormal YoungFour Figures
Warkany, J., & Roth, C. (1948) · Journal of Nutrition · doi:10.1093/jn/35.1.1 · Cited by 134 · see citing works
Synthesis of some Compounds Possessing Vitamin A Activity
Arens, J. F., & Dorp, D. A. V. (1946) · Nature · doi:10.1038/157190a0 · Cited by 133 · cited 1× · see citing works
“In 1946, Arens and van Dorp synthesized vitamin A acid (retinoic acid), and reported it was as potent as vitamin A in supporting the growth of VAD rats but could not be converted back to vitamin A [8–10].”
Background
Teratogen-induced, dietary and genetic models of congenital diaphragmatic hernia share a common mechanism of pathogenesis.
Clugston, R. D., Klattig, J., Englert, C., Clagett-Dame, M., Martinovic, J., Benachi, A., & Greer, J. (2006) · American Journal of Pathology · doi:10.2353/ajpath.2006.060445 · Cited by 131 · cited 1× · see citing works
“5 in vitamin A-sufficient rat embryos, but it is abnormal in late VAD embryos [252].”
BackgroundSelf-citation
Dhrs3a Regulates Retinoic Acid Biosynthesis through a Feedback Inhibition Mechanism
Feng, L., Hernandez, R., Waxman, J., Yelon, D., & Moens, C. (2009) · Developmental Biology · doi:10.1016/j.ydbio.2009.10.029 · Cited by 128 · cited 1× · see citing works
“member, DHRS3a, which catalyzes reduction of retinaldehyde to retinol serving as a RA-induced feedback inhibitor of RA biosynthesis [138].”
Background
Developmental abnormalities in cultured mouse embryos deprived of retinoic by inhibition of yolk-sac retinol binding protein synthesis.
Båvik, C., Ward, S. J., & Chambon, P. (1996) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.93.7.3110 · Cited by 126 · cited 13× · see citing works
“Retinol-binding protein (RBP or RBP4) carries the majority of retinol in the circulation [25], and a membrane receptor, STRA6, binds to RBP to enable efficient retinol uptake by a number of cells [26].”
BackgroundInfluential
Active repression of RAR signaling is required for head formationPreprint
Koide, T., Downes, M., Chandraratna, R. A. S., Blumberg, B., & Umesono, K. (2001) · Genes & Development · doi:10.1101/gad.908801 · Cited by 125 · cited 1× · see citing works
“should remain off [175].”
Role of retinoic acid during forebrain development begins late when Raldh3 generates retinoic acid in the ventral subventricular zone.
Molotkova, N., Molotkov, A., & Duester, G. (2007) · Developmental Biology · doi:10.1016/j.ydbio.2006.11.035 · Cited by 124 · cited 2× · see citing works
“Instead, Molotkova and colleagues propose that RA functions at later times in forebrain development, and provide evidence that RA generated by RALDH3 in the lateral ganglionic eminence is required for normal expression of the dopamine D2 receptor in the nucleus accumbens and medial striatum [180].”
Background
Prepubertal testis development relies on retinoic acid but not rexinoid receptors in Sertoli cells
Vernet, N., Dennefeld, C., Guillou, F., Chambon, P., Ghyselinck, N., & Mark, M. (2006) · EMBO Journal · doi:10.1038/sj.emboj.7601447 · Cited by 124 · cited 1× · see citing works
“Expression of RARα is needed for differentiation of the spermatogonia during prepuberty [55].”
Background
Retinoic acid receptor-β: an endogenous inhibitor of the perinatal formation of pulmonary alveoli
Massaro, G., Massaro, D., Chan, W., Clerch, L., Ghyselinck, N., Chambon, P., & Chandraratna, R. (2000) · Physiological Genomics · doi:10.1152/physiolgenomics.2000.4.1.51 · Cited by 121 · cited 1× · see citing works
“reports that exogenous RA can stimulate alveoli formation in immature rat and mouse lung [264–269].”
Background
Identification of endogenous retinoids, enzymes, binding proteins, and receptors during early postimplantation development in mouse: important role of retinal dehydrogenase type 2 in synthesis of all-trans-retinoic acid.
Ulven, S., Gundersen, T. E., Weedon, M. S., Landaas, V. Ø., Sakhi, A., Fromm, S., Geronimo, B., Moskaug, J. Ø., & Blomhoff, R. (2000) · Developmental Biology · doi:10.1006/dbio.2000.9634 · Cited by 121 · cited 1× · see citing works
“Using direct identification by HPLC, all-trans retinaldehyde is detected in embryos as early as the egg cylinder or pre-primitive streak stage, whereas RA is detected between the mid-primitive streak stage and the late allantoic bud stage [146].”
Method
Zur Kenntnis des Vitamins-A aus Fischtranen
Karrer, P., Morf, R., & Schopp, K. (1931) · Helvetica Chimica Acta · doi:10.1002/hlca.19310140511 · Cited by 121 · see citing works
Retinoids and mammalian development.
Morriss-Kay, G., & Ward, S. (1999) · International Review of Cytology · doi:10.1016/s0074-7696(08)61566-1 · Cited by 120 · cited 2× · see citing works
“Retinol-binding protein (RBP or RBP4) carries the majority of retinol in the circulation [25], and a membrane receptor, STRA6, binds to RBP to enable efficient retinol uptake by a number of cells [26].”
Background
Essential roles of retinoic acid signaling in interdigital apoptosis and control of BMP-7 expression in mouse autopods.
Dupé, V., Ghyselinck, N., Thomázy, V. A., Nagy, L., Davies, P. J. A., Chambon, P., & Mark, M. (1999) · Developmental Biology · doi:10.1006/dbio.1998.9176 · Cited by 119 · cited 1× · see citing works
“Webbed digits have been described in compound RAR mutant mice due to a loss of apoptosis [209,294].”
Background
Histology of the lesions produced in the reproductive tract of animals fed a diet deficient in vitamin A alcohol but containing vitamin A acid. I. The male rat.
Howell, J., Thompson, J. N., & Pitt, G. A. (1963) · Journal of Reproduction and Fertility · doi:10.1530/jrf.0.0050159 · Cited by 118 · cited 1×
“insufficient amounts of RA [68].”
Elevations in the endogenous levels of the putative morphogen retinoic acid in embryonic mouse limb-buds associated with limb dysmorphogenesis.
Satre, M., & Kochhar, D. (1989) · Developmental Biology · doi:10.1016/0012-1606(89)90055-9 · Cited by 117 · cited 1× · see citing works
“HPLC studies of embryonic tissues at later times confirm that all-trans retinol and RA are the primary retinoids detected, with retinol clearly the most abundant [153–155].”
Background
Endogenous retinoic acid regulates cardiac progenitor differentiation
Lin, S.-C., Dollé, P., Ryckebusch, L., Noseda, M., Zaffran, S., Schneider, M., & Niederreither, K. (2010) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.0910430107 · Cited by 115 · cited 1× · see citing works
“heart tube patterning and looping, chamber and outflow tract septation, ventricular trabeculation, cardiomyocyte differentiation and coronary vessel development [231–233].”
Background
Early mouse caudal development relies on crosstalk between retinoic acid,Shh and Fgf signalling pathways
Ribes, V., Roux, I. L., Rhinn, M., Schuhbaur, B., & Dollé, P. (2009) · Development · doi:10.1242/dev.016204 · Cited by 114 · cited 3× · see citing works
“mesodermal markers are expanded at the expense of those representative of the prospective neuroepithelium [149].”
Background
A conserved role for retinoid signaling in vertebrate pancreas development
Stafford, D. A., Hornbruch, A., Mueller, P. R., & Prince, V. (2004) · Development, Genes and Evolution · doi:10.1007/s00427-004-0420-6 · Cited by 114 · cited 2× · see citing works
“null mutant mice, a requirement for RA in pancreatic development has been proposed based on studies in RALDH null mutant mice [271,272] and in several other organisms in which retinoid signaling is deficient or inhibited, including Xenopus, zebrafish, chick, and quail [273–276].”
Background
Retinol-binding protein and transthyretin mRNA levels in visceral yolk sac and liver during fetal development in the rat.
Soprano, D., Soprano, K., & Goodman, D. (1986) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.83.19.7330 · Cited by 114 · cited 1× · see citing works
“endoderm of the yolk sac visceral wall surrounding the embryo, and after definitive placentation, in the yolk sac membranes as well as in the uterus (decidua basalis) [111,112].”
Background
Signaling hierarchy downstream of retinoic acid that independently regulates vascular remodeling and endothelial cell proliferationPreprint
Bohnsack, B. L., Lai, L., Dollé, P., & Hirschi, K. K. (2004) · Genes & Development · doi:10.1101/gad.1184904 · Cited by 112 · cited 1× · see citing works
“Raldh2 in the embryo, along with expression in the visceral endoderm (extraembryonic) is required for vascular development in both the embryo proper, as well as the yolk sac [150–152].”
Background
Requirement of mesodermal retinoic acid generated by Raldh2 for posterior neural transformation
Molotkova, N., Molotkov, A., Sîrbu, I. O., & Duester, G. (2004) · Mechanisms of Development · doi:10.1016/j.mod.2004.10.008 · Cited by 112 · cited 1× · see citing works
“Although primary neurulation occurs in both RALDH2 mutant mice and VAD chick and rat embryos [65,123,187], the”
Background
Retinoids and spinal cord development.
Maden, M. (2006) · Journal of Neurobiology · doi:10.1002/neu.20248 · Cited by 111 · cited 1× · see citing works
“Induction of more posterior domains occurs by the actions of RA, Wnts and FGFs, with RA specifying the posterior hindbrain and cervical spinal cord [160].”
Background
Induction and prepatterning of the zebrafish pectoral fin bud requires axial retinoic acid signaling
Gibert, Y., Gajewski, A., Meyer, A., & Begemann, G. (2006) · Development · doi:10.1242/dev.02438 · Cited by 110 · cited 2× · see citing works
“, who found that axial retinoic acid signals played a permissive role in the induction of zebrafish pectoral fins [289].”
Background
Retinoic Acid Synthesis Controlled by Raldh2 Is Required Early for Limb Bud Initiation and Then Later as a Proximodistal Signal during Apical Ectodermal Ridge Formation*
Mic, F., Sirbu, I. O., & Duester, G. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m401920200 · Cited by 110 · cited 1× · see citing works
“of RALDH2, murine forelimb buds do not develop and embryonic growth ceases prior to the stage when hindlimb buds are initiated [287,288].”
Background
Retinoic acid regulates programmed cell death through BMP signalling
Rodríguez-León, J., Merino, R., Macías, D., Gańan, Y., Santesteban, E., & Hurlé, J. (1999) · Nature Cell Biology · doi:10.1038/10098 · Cited by 110 · cited 1× · see citing works
“The mechanism by which RA activates cell death is currently a subject of active investigation [294–297].”
Background
Increased Neonatal Mortality in Mice Lacking Cellular Retinol-binding Protein II*
E, X., Zhang, L., Lu, J.-Y., Tso, P., Blaner, W., Levin, M., & Li, E. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m205519200 · Cited by 108 · cited 1× · see citing works
“mice; some have been found to be dispensable, while roles for others have been revealed when animals are fed a vitamin A-restricted diet [12,27,28].”
Background
Retinoic Acid Availability Drives the Asynchronous Initiation of Spermatogonial Differentiation in the Mouse1
Snyder, E. M., Small, C., & Griswold, M. (2010) · Biology of Reproduction · doi:10.1095/biolreprod.110.085811 · Cited by 107 · cited 1× · see citing works
“Recent work supports the conclusion that the vitamin A metabolite, RA, is needed both for adult male spermatogonial differentiation (transition to A1) and the entrance into meiosis [45–47].”
Result
Maternal vitamin A supplementation and lung function in offspring.
Checkley, W., West, K., Wise, R., Baldwin, M., Wu, L. S. F., Leclerq, S., Christian, P., Katz, J., Tielsch, J., Khatry, S., et al. (2010) · New England Journal of Medicine · doi:10.1056/nejmoa0907441 · Cited by 107 · see citing works
Retinoic acid signaling in perioptic mesenchyme represses Wnt signaling via induction of Pitx2 and Dkk2
Kumar, S., & Duester, G. (2010) · Developmental Biology · doi:10.1016/j.ydbio.2010.01.027 · Cited by 106 · cited 2× · see citing works
“Defects result from the loss of control of programmed cell death in this region, and by loss of RA-mediated Pitx2, Foxc1, Eya2 and Dkk2 expression, and subsequent loss of repression of Wnt/β-catenin signaling [134,135,212,214].”
Background
Retinoids control anterior and dorsal properties in the developing forebrain.
Halilagic, A., Ribes, V., Ghyselinck, N., Zile, M., Dollé, P., & Studer, M. (2007) · Developmental Biology · doi:10.1016/j.ydbio.2006.11.021 · Cited by 106 · cited 3× · see citing works
“A number of eye defects in RALDH3 and RALDH1/3 compound mutants [134,135,178] are also similar to those observed in late VAD rat embryos.”
Background
Distinct Retinoid Metabolic Functions for Alcohol Dehydrogenase Genes Adh1 and Adh4 in Protection against Vitamin A Toxicity or Deficiency Revealed in Double Null Mutant Mice
Molotkov, A., Deltour, L., Foglio, M. H., Cuenca, A. E., & Duester, G. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m112039200 · Cited by 105 · cited 1× · see citing works
“Adh 1, 3 and 4 enzyme family members are also expressed in developing embryos [126,127], however, mutation does not result in embryo lethality [128,129].”
Background
How degrading: Cyp26s in hindbrain development
White, R. J., & Schilling, T. F. (2008) · Developmental Dynamics · doi:10.1002/dvdy.21695 · Cited by 105 · cited 2× · see citing works
“developing hindbrain all include an important role for CYP26 family members in regulating the formation of waves or pulses of RA in this dynamic process [23,144,172,173].”
Background
Impairing retinoic acid signalling in the neural crest cells is sufficient to alter entire eye morphogenesis.
Matt, N., Ghyselinck, N., Pellerin, I., & Dupé, V. (2008) · Developmental Biology · doi:10.1016/j.ydbio.2008.04.039 · Cited by 103 · see citing works
Distinct roles for retinoic acid receptors alpha and beta in early lung morphogenesis.
Desai, T. J., Chen, F., Lu, J.-N., Qian, J., Niederreither, K., Dollé, P., Chambon, P., & Cardoso, W. (2006) · Developmental Biology · doi:10.1016/j.ydbio.2005.10.045 · Cited by 103 · see citing works
MULTIPLE CONGENITAL MALFORMATIONS: A CONSIDERATION OF ETIOLOGIC FACTORS
Warkany, J., Roth, C., & Wilson, J. G. (1948) · Pediatrics · doi:10.1542/peds.1.4.462 · Cited by 103 · cited 1× · see citing works
“Respiratory defects including left lung agenesis, bilateral lung hypoplasia, and agenesis of the esophagotracheal septum were described in early VAD syndrome embryos but were characterized as rare anomalies [90,95].”
Background
Retinol Status of Newborn Infants Is Associated With Congenital Diaphragmatic Hernia
Beurskens, L., Tibboel, D., Lindemans, J., Duvekot, J., Cohen-Overbeek, T., Veenma, D., de Klein, A., Greer, J., & Steegers-Theunissen, R. (2010) · Pediatrics · doi:10.1542/peds.2010-0521 · Cited by 102 · cited 1× · see citing works
“A recent report shows that there is a relationship between low cord retinol and RBP levels and CDH in newborn infants [249].”
Background
All-trans-retinol is a ligand for the retinoic acid receptors.
Repa, J., Hanson, K. K., & Clagett-Dame, M. (1993) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.90.15.7293 · Cited by 99 · cited 1× · see citing works
“The all-trans isomer of RA is the highest affinity endogenous ligand for the RAR [31].”
BackgroundSelf-citation
Raldh2 expression in optic vesicle generates a retinoic acid signal needed for invagination of retina during optic cup formation
Mic, F. A., Molotkov, A., Molotkova, N., & Duester, G. (2004) · Developmental Dynamics · doi:10.1002/dvdy.20128 · Cited by 96 · cited 1× · see citing works
“5 [132,148,203], after which Raldh3 (also called V1 activity) is expressed in the ventral neural retina and pigmented neuroepithelium [134,204–206] and Raldh1 (also called ADH-2) is expressed in the dorsal retina from E9.”
Background
Cytological changes in the testes of vitamin-A-deficient rats. I. Quantitation of germinal cells in the seminiferous tubules.
Mitranond, V., Sobhon, P., Tosukhowong, P., & Chíndaduangrat, W. (1979) · Acta Anatomica · doi:10.1159/000145007 · Cited by 94 · see citing works
Delivery of retinoid-based therapies to target tissues
Moise, A. R., Noy, N., Palczewski, K., & Blaner, W. S. (2007) · Biochemistry · doi:10.1021/bi7003069 · Cited by 93 · cited 2× · see citing works
“mice; some have been found to be dispensable, while roles for others have been revealed when animals are fed a vitamin A-restricted diet [12,27,28].”
Background
Cyp26b1 Expression in Murine Sertoli Cells Is Required to Maintain Male Germ Cells in an Undifferentiated State during Embryogenesis
Li, H., Maclean, G., Cameron, D., Clagett-Dame, M., & Petkovich, M. (2009) · PLoS ONE · doi:10.1371/journal.pone.0007501 · Cited by 92 · cited 1× · see citing works
“CYP26B1 is also required later in embryogenesis to maintain cells in an undifferentiated state [82].”
BackgroundSelf-citation
Retinol dehydrogenase 10 is a feedback regulator of retinoic acid signalling during axis formation and patterning of the central nervous system
Strate, I., Grahn, T. H. M., Iliev, D., & Pera, E. M. (2009) · Development · doi:10.1242/dev.024901 · Cited by 91 · cited 1× · see citing works
“Recent work in Xenopus shows that RA down regulates XRDH10 transcripts, and this may serve as an additional mechanism to regulate endogenous retinoid levels [125].”
Background
Transplacental delivery of retinoid: the role of retinol-binding protein and lipoprotein retinyl ester.
Quadro, L., Hamberger, L., Gottesman, M., Colantuoni, V., Ramakrishnan, R., & Blaner, W. (2004) · American Journal of Physiology. Endocrinology and Metabolism · doi:10.1152/ajpendo.00556.2003 · Cited by 90 · cited 2× · see citing works
“RBP does not cross the placenta into the fetal circulation [113].”
Background
Stage-dependent responses of the developing lung to retinoic acid signaling.
Mollard, R., Ghyselinck, N., Wendling, O., Chambon, P., & Mark, M. (2000) · International Journal of Developmental Biology · doi:10.1387/ijdb.11032179 · Cited by 90 · cited 1× · see citing works
“RA acting through the RAR is also necessary for the morphogenesis of other components of the respiratory tract including partitioning of the primitive foregut into oesophagus and trachea, and for the opening between the nasal and oropharyngeal cavities [67,131,209,256,258,261].”
Background
Retinoic acid synthesis for the developing telencephalon.
Smith, D., Wagner, E., Koul, O., McCaffery, P., & Dräger, U. C. (2001) · Cerebral Cortex · doi:10.1093/cercor/11.10.894 · Cited by 88 · cited 1× · see citing works
“In the meninges covering the cortex, levels of Raldh2 increase in the mouse embryo from E13 to E14 onward, to a maximal level in the newborn brain [184].”
Background
Retinaldehyde dehydrogenase 2 and Hoxc8 are required in the murine brachial spinal cord for the specification of Lim1+ motoneurons and the correct distribution of Islet1+ motoneurons
Vermot, J., Schuhbaur, B., Mouellic, H. L., McCaffery, P., Garnier, J., Hentsch, D., Brûlet, P., Niederreither, K., Chambon, P., Dollé, P., et al. (2005) · Development · doi:10.1242/dev.01718 · Cited by 86 · see citing works
Expression patterns of class I and class IV alcohol dehydrogenase genes in developing epithelia suggest a role for alcohol dehydrogenase in local retinoic acid synthesis.
Ang, H., Deltour, L., Žgombic-Knight, M., Wagner, M., & Duester, G. (1996) · Alcoholism: Clinical and Experimental Research · doi:10.1111/j.1530-0277.1996.tb01946.x · Cited by 86 · cited 1× · see citing works
“Adh 1, 3 and 4 enzyme family members are also expressed in developing embryos [126,127], however, mutation does not result in embryo lethality [128,129].”
Background
Maternal Vitamin A Supplementation and Lung Function in Offspring
Shulman, L. (2010) · doi:10.1016/s1090-798x(10)79165-7 · Cited by 86 · cited 1×
“Additionally, they found that the period during which supplementation with vitamin A was most important was from gestation through a postnatal age of 6 months [270].”
Background
Genetic disruption of CYP26B1 severely affects development of neural crest derived head structures, but does not compromise hindbrain patterning
Maclean, G., Dollé, P., & Petkovich, M. (2009) · Developmental Dynamics · doi:10.1002/dvdy.21878 · Cited by 85 · cited 2× · see citing works
“character [139,140], however, individual CYP26B1 and CYP26C1 mutants develop normally [143,144].”
Background
Retinoids and spermatogenesis: Lessons from mutant mice lacking the plasma retinol binding protein
Ghyselinck, N. B., Vernet, N., Dennefeld, C., Giese, N., Nau, H., Chambon, P., Viville, S., & Mark, M. P. (2006) · Developmental Dynamics · doi:10.1002/dvdy.20795 · Cited by 84 · cited 14× · see citing works
“In the mouse, Raldh2 (also called V2 activity) is transiently expressed in the optic vesicle neuroepithelium at E8.”
BackgroundInfluential
The atRA Regulated Gene Neuron Navigator 2 Functions in Neurite Outgrowth and Axonal Elongation
Muley, P. D., McNeill, E., Marzinke, M., Knobel, K. M., Barr, M., & Clagett-Dame, M. (2008) · Developmental Neurobiology · doi:10.1002/dneu.20670 · Cited by 84 · cited 1× · see citing works
“When NAV2 is knocked down, the neuroblastoma cell is no longer able to extend neurites in response to RA [201].”
BackgroundSelf-citation
Signal Transduction in Early Heart Development (II): Ventricular Chamber Specification, Trabeculation, and Heart Valve Formation
Wagner, M., & Siddiqui, M. (2007) · Experimental biology and medicine · doi:10.3181/00379727-232-2320866 · Cited by 80 · cited 1×
“heart tube patterning and looping, chamber and outflow tract septation, ventricular trabeculation, cardiomyocyte differentiation and coronary vessel development [231–233].”
Background
Expression of murineLhx5 suggests a role in specifying the forebrain
SHENG, H. Z., Bertuzzi, S., Chiang, C. C., Shawlot, W., Taira, M., Dawid, I. B., & Westphal, H. (1997) · Developmental Dynamics · doi:10.1002/(sici)1097-0177(199702)208:2 · Cited by 78 · see citing works
All-trans retinoic acid induces differentiation of ducts and endocrine cells by mesenchymal/epithelial interactions in embryonic pancreas.
Tulachan, S., Doi, R., Kawaguchi, Y., Tsuji, S., Nakajima, S., Masui, T., Koizumi, M., Toyoda, E., Mori, T., Ito, D., et al. (2003) · Diabetes · doi:10.2337/diabetes.52.1.76 · Cited by 78 · cited 2× · see citing works
“Both defects in RA signaling and RA treatment have been shown to affect the expression of PDX-1 [271,272,275,278] an essential regulator of early pancreas development required for the”
Background
The Meninges Is a Source of Retinoic Acid for the Late-Developing Hindbrain
Zhang, J., Smith, D. F., Yamamoto, M., Ma, L., & McCaffery, P. J. A. (2003) · Journal of Neuroscience · doi:10.1523/jneurosci.23-20-07610.2003 · Cited by 78 · cited 1× · see citing works
“pontine nuclei [182].”
Blood island formation in attached cultures of murine embryonic stem cells
Bautch, V. L., Stanford, W. L., Rapoport, R., Russell, S., Byrum, R. S., & Futch, T. A. (1996) · Developmental Dynamics · doi:10.1002/(sici)1097-0177(199601)205:1 · Cited by 78 · see citing works
Self-citation
A nutritional model of late embryonic vitamin A deficiency produces defects in organogenesis at a high penetrance and reveals new roles for the vitamin in skeletal development.
See, A. M., Kaiser, M., White, J. C., & Clagett-Dame, M. (2008) · Developmental Biology · doi:10.1016/j.ydbio.2007.10.018 · Cited by 77 · cited 10× · see citing works
“5 in the rat embryo, a time when the cardiac primordium has completed looping and the primitive vasculature is established, early cardiac and aortic arch defects are not observed [67].”
BackgroundInfluentialSelf-citation
Cardiac and aortic arch anomalies in the offspring of vitamin A deficient rats correlated with similar human anomalies.
Wilson, J. G., & Warkany, J. (1950) · Pediatrics · doi:10.1542/peds.5.4.708 · Cited by 77 · cited 1× · see citing works
“Cardiac and aortic arch defects were observed as a part of the early vitamin A deficiency syndrome in rat embryos [93,94] and in RAR compound null mutant mouse embryos [98,102].”
Background
Retinoic acid signalling specifies intermediate character in the developing telencephalon
Marklund, M., Sjödal, M., Beehler, B. C., Jessell, T. M., Edlund, H., & Gunhaga, L. (2004) · Development · doi:10.1242/dev.01308 · Cited by 76 · cited 1× · see citing works
“RA was also reported in chick to contribute to regionalization of the telencephalon along the dorsoventral axis, and RALDH3 produced by the head ectoderm was proposed as the retinoid source [179].”
Background
Understanding Abnormal Retinoid Signaling as a Causative Mechanism in Congenital Diaphragmatic Hernia
Clugston, R. D., Zhang, W., Álvarez, S., de Lera, Á. R., & Greer, J. J. (2009) · American Journal of Respiratory Cell and Molecular Biology · doi:10.1165/rcmb.2009-0076oc · Cited by 76 · cited 1× · see citing works
“Similar defects in PPF development are seen in rat embryos treated with nitrofen and several other CDH-inducing teratogens that interfere with the synthesis of RA and RA signaling in vivo [253,254].”
Background
Vitamin A from fishoils. 2.
Karrer, P., Morf, R., & Schopp, K. (1931) · Helvetica Chimica Acta · doi:10.1002/hlca.19310140622 · Cited by 75 · see citing works
Vitamin A Deficiency Results in Meiotic Failure and Accumulation of Undifferentiated Spermatogonia in Prepubertal Mouse Testis1
Li, H., Palczewski, K., Baehr, W., & Clagett-Dame, M. (2011) · Biology of Reproduction · doi:10.1095/biolreprod.110.086157 · Cited by 71 · cited 1× · see citing works
“showed that vitamin A is required in the male neonate for germ cells to enter the first round of spermatogenesis [83].”
BackgroundSelf-citation
A mammalian homolog of unc-53 is regulated by all-trans retinoic acid in neuroblastoma cells and embryos
Merrill, R. A., Plum, L., Kaiser, M., & Clagett-Dame, M. (2002) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.052017399 · Cited by 71 · cited 1× · see citing works
“Recently, a number of genes including neuron navigator 2 (Nav2) and Nedd9 were discovered in a screen for RA-responsive genes in a neuroblastoma cell line that elaborates neurites in response to RA [198–200].”
BackgroundSelf-citation
The temporal requirement for vitamin A in the developing eye: Mechanism of action in optic fissure closure and new roles for the vitamin in regulating cell proliferation and adhesion in the embryonic retina
See, A. W., & Clagett‐Dame, M. (2008) · Developmental Biology · doi:10.1016/j.ydbio.2008.09.030 · Cited by 71 · cited 4× · see citing works
“the conjunctival sac, folding of the retina, absence of the vitreous body and the presence of a fibrous retrolenticular membrane [67,104].”
BackgroundInfluentialSelf-citation
Vitamin A Deficiency Blocks the Initiation of Meiosis of Germ Cells in the Developing Rat Ovary In Vivo1
Li, H., & Clagett-Dame, M. (2009) · Biology of Reproduction · doi:10.1095/biolreprod.109.078808 · Cited by 70 · cited 1× · see citing works
“There is clear in vivo evidence that vitamin A is required for the normal onset of meiotic prophase in ovarian germ cells [79].”
BackgroundSelf-citation

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Research works printed but not linked: 49

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Sorted by citations

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EFSA Panel on Dietetic Products, N. (2015) · EFSA Journal · doi:10.2903/j.efsa.2015.4028 · Cited by 240 · see citing works
“The main symptoms observed in case of deficiency of vitamin A are intrauterine and post-natal growth retardation and a large array of congenital malformations collectively referred to as the fetal “vitamin A deficiency syndrome”, which is well documented in animals (Clagett-Dame and Knutson, 2011).”
Background
Retinoic acid signaling pathways in development and diseases
Das, B. C., Thapa, P., Karki, R., Das, S., Mahapatra, S., Liu, T.-C., Torregroza, I., Wallace, D. P., Kambhampati, S., Van Veldhuizen, P., et al. (2014) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2013.11.025 · Cited by 276 · see citing works
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“Vitamin A is not only essential for both male and female reproduction processes (Clagett-Dame and Knutson, 2011), it is also crucial for the prevention of malformations, the maintenance of vertebral identity, and for the development of skeletal elements during embryogenesis (Baume et al.”
BackgroundInfluential
Influence of chromoplast morphology on carotenoid bioaccessibility of carrot, mango, papaya, and tomato.
Schweiggert, R., Mezger, D., Schimpf, F., Steingass, C., & Carle, R. (2012) · Food Chemistry · doi:10.1016/j.foodchem.2012.07.035 · Cited by 208 · see citing works
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“The systemic administration of RAs has been shown to reverse most reproductive and developmental blocks in vitamin A deficient (VAD) rats and mice, demonstrating that retinoid signaling rescues reproductive defects as well as steroidogenesis in VAD animals [201, 207, 208].”
Background
Enzymology of retinoic acid biosynthesis and degradation
Kedishvili, N. Y. (2013) · Journal of Lipid Research · doi:10.1194/jlr.r037028 · Cited by 196 · see citing works
Vitamin A Deficiency and the Lung
Timoneda, J., Rodríguez‐Fernández, L., Zaragozá, R., Marín, M., Cabezuelo, M. A., Torres, L., Vinã, J. R., & Barber, T. (2018) · Nutrients · doi:10.3390/nu10091132 · Cited by 214 · see citing works
On the role of skin in the regulation of local and systemic steroidogenic activities
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Microencapsulation of vitamin A: A review
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Regulation of human hematopoietic stem cell self-renewal by the microenvironment’s control of retinoic acid signaling
Ghiaur, G., Yegnasubramanian, S., Perkins, B. N., Gucwa, J. L., Gerber, J. M., & Jones, R. J. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1305937110 · Cited by 136 · see citing works
“Although RA signaling is essential for the homeostasis of diverse biological systems (5), its role in hematopoiesis, and HSC biology in particular, is still unclear.”
Background
Impact of oxidative stress on oocyte competence for in vitro embryo production programs.
Soto-Heras, S., & Paramio, M. (2020) · Research in Veterinary Science · doi:10.1016/j.rvsc.2020.07.013 · Cited by 134 · see citing works
The retinaldehyde reductase DHRS3 is essential for preventing the formation of excess retinoic acid during embryonic development
Billings, S. E., Pierzchalski, K., Tjaden, N. E. B., Pang, X.-Y., Trainor, P., Kane, M. A., & Moise, A. (2013) · The FASEB Journal · doi:10.1096/fj.13-227967 · Cited by 120 · see citing works
“Thus, DHRS3 is found in many embryonic tissues where retinoid metabolism and retinoid signaling play important roles (1, 2, 64).”
Background
Mechanistic aspects of carotenoid health benefits – where are we now?
Bohn, T., Bonet, M. L., Borel, P., Keijer, J., Landrier, J., Milisav, I., Ribot, J., Riso, P., Winklhofer-Roob, B., Sharoni, Y., et al. (2021) · Nutrition Research Reviews · doi:10.1017/s0954422421000147 · Cited by 151 · see citing works
“importance for processes of embryonic development(362,363), reproduction(364,365), epidermal homeostasis and regeneration(366,367), immune responses(368,369) and maintenance of bone, brain, nervous and cardiovascular functions(370–372).”
Background
Role of Vitamin A/Retinoic Acid in Regulation of Embryonic and Adult Hematopoiesis
Cañete, A., Cano, E., Muñoz‐Chápuli, R., & Carmona, R. (2017) · Nutrients · doi:10.3390/nu9020159 · Cited by 117 · see citing works
“In the nucleus, the RAR/RXR complex is bound to a specific sequence of DNA (RARE: retinoic acid response element) and usually performs repressor roles in the absence of ligands, activating transcription of target genes when bound to them ([16,17]) (Figure 1).”
Background
RDH10 Oxidation of Vitamin A Is a Critical Control Step in Synthesis of Retinoic Acid during Mouse Embryogenesis
Sandell, L. L., Lynn, M., Inman, K., McDowell, W., & Trainor, P. (2012) · PLoS ONE · doi:10.1371/journal.pone.0030698 · Cited by 103 · see citing works
“Retinoic acid (RA) is a derivative of Vitamin A (retinol) that plays an essential role in many vertebrate biological processes including energy metabolism, brain function, immune response, reproduction and embryonic development (reviewed in [1,2,3, 4,5,6]).”
Background
The Retinaldehyde Reductase Activity of DHRS3 Is Reciprocally Activated by Retinol Dehydrogenase 10 to Control Retinoid Homeostasis*
Adams, M. K., Belyaeva, O., Wu, L., & Kedishvili, N. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m114.552257 · Cited by 98 · see citing works
Retinoic acid signaling and mouse embryonic stem cell differentiation: Cross talk between genomic and non-genomic effects of RA
Rochette‐Egly, C. (2014) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/j.bbalip.2014.04.003 · Cited by 97 · see citing works
Retinol dehydrogenase 10 is indispensible for spermatogenesis in juvenile males
Tong, M.-H., Yang, Q.-E., Davis, J. C., & Griswold, M. (2012) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.1214883110 · Cited by 95 · see citing works
A retinoic acid receptor RARα pool present in membrane lipid rafts forms complexes with G protein αQ to activate p38MAPK
Piskunov, A., & Rochette-Egly, C. (2012) · Oncogene · doi:10.1038/onc.2011.499 · Cited by 95 · see citing works
“Retinoic acid (RA), a pleiotropic signaling molecule derived from vitamin A, regulates critical genetic programs that control development and homeostasis, cell proliferation and differentiation, as well as cell death or survival (Clagett-Dame and Knutson, 2011).”
Background
Molecular regulation of the mitosis/meiosis decision in multicellular organisms.
Kimble, J. (2011) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a002683 · Cited by 93
“is that VAD blocks meiotic entry (Bowles and Koopman 2007; Clagett-Dame and Knutson 2011).”
Immune Impairment Associated with Vitamin A Deficiency: Insights from Clinical Studies and Animal Model Research
Amimo, J. O., Michael, H., Chepngeno, J., Raev, S. A., Saif, L. J., & Vlasova, A. N. (2022) · Nutrients · doi:10.3390/nu14235038 · Cited by 105 · see citing works
“VA importance in reproduction and embryo development was demonstrated in studies showing that VAD female rats had difficulty becoming pregnant and that those that became pregnant produced pups with birth defects [50].”
Background
Lutein, zeaxanthin and mammalian development: metabolism, functions and implications for health
Giordano, E., & Quadro, L. (2018) · Archives of Biochemistry and Biophysics · doi:10.1016/j.abb.2018.04.008 · Cited by 90 · see citing works
“The essential nutrient vitamin A indeed supports proper mammalian development by exerting critical transcriptional regulatory activities mediated by its active form retinoic acid (18, 19).”
Background
Inhibition of Retinoic Acid Biosynthesis by the Bisdichloroacetyldiamine WIN 18,446 Markedly Suppresses Spermatogenesis and Alters Retinoid Metabolism in Mice*
Paik, J., Haenisch, M., Muller, C., Goldstein, A., Arnold, S. L. M., Isoherranen, N., Brabb, T., Treuting, P., & Amory, J. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.540211 · Cited by 84 · see citing works
“In males, either vitamin A deficiency (3) or mutations in genes involved in retinoid signaling pathways leads to perturbations in meiosis and spermatogenesis (1, 2).”
Background
Vitamin A production by engineered Saccharomyces cerevisiae from xylose via two-phase in situ extraction.
Sun, L., Kwak, S., & Jin, Y.-S. (2019) · ACS Synthetic Biology · doi:10.1021/acssynbio.9b00217 · Cited by 81 · see citing works
Molecular and Cellular Mechanisms of Intramuscular Fat Development and Growth in Cattle
Tan, Z., & Jiang, H. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25052520 · Cited by 85 · see citing works
“Vitamin A is a fat-soluble vitamin crucial for maintaining normal growth and development, immune system function, vision, skin health, and reproduction [114].”
Background
Involvement of multiple phytoene synthase genes in tissue- and cultivar-specific accumulation of carotenoids in loquat
Fu, X.-M., Feng, C., Wang, C.-Y., Yin, X.-R., Lu, P., Grierson, D., Xu, C.-J., & Chen, K.-S. (2014) · Journal of Experimental Botany · doi:10.1093/jxb/eru257 · Cited by 80
Fat-soluble vitamins: updated review of their role and orchestration in human nutrition throughout life cycle with sex differences
Youness, R. A., Dawoud, A., Eltahtawy, O., & Farag, M. A. (2022) · Nutrition & Metabolism · doi:10.1186/s12986-022-00696-y · Cited by 99 · see citing works
Naturally Occurring Antioxidant Therapy in Alzheimer’s Disease
Collins, A. E., Saleh, T. M., & Kalisch, B. E. (2022) · Antioxidants · doi:10.3390/antiox11020213 · Cited by 87 · see citing works
“Vitamin A maintains essential roles in vision and synaptic function [58], bone growth and development [59], gene expression [60], cell division [61], reproduction [62], the maintenance of epithelial cells in respiratory, intestinal and urinary tracts, and a healthy immune system [63,64].”
Background
Retinoids in health and disease: A role for hepatic stellate cells in affecting retinoid levels
Haaker, M. W., Vaandrager, A. B., & Helms, J. B. (2020) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/j.bbalip.2020.158674 · Cited by 84 · see citing works
Importance of ALDH1A enzymes in determining human testicular retinoic acid concentrations
Arnold, S. L. M., Kent, T., Hogarth, C., Schlatt, S., Prasad, B., Haenisch, M., Walsh, T., Muller, C., Griswold, M., Amory, J., et al. (2015) · Journal of Lipid Research · doi:10.1194/jlr.m054718 · Cited by 72 · see citing works
Utilization of Nanotechnology to Improve the Handling, Storage and Biocompatibility of Bioactive Lipids in Food Applications
McClements, D. J., & Öztürk, B. (2021) · Foods · doi:10.3390/foods10020365 · Cited by 107 · see citing works
“Vitamin A is known to improve visual health, help reproduction, boost the immune system, and promote growth [21].”
Background
Molecular Basis for Vitamin A Uptake and Storage in Vertebrates
Chelstowska, S., Widjaja-Adhi, M., Silvaroli, J., & Golczak, M. (2016) · Nutrients · doi:10.3390/nu8110676 · Cited by 69 · see citing works
Metabolic and functional interplay between gut microbiota and fat-soluble vitamins
Stacchiotti, V., Rezzi, S., Eggersdorfer, M. L., & Galli, F. (2020) · Critical Reviews in Food Science and Nutrition · doi:10.1080/10408398.2020.1793728 · Cited by 83 · see citing works
“These bind specific DNA sequences, e.g., the RA response elements, thereby activating transcription of target genes (i.e., genes of immune response and reproduction) (Clagett-Dame and Knutson 2011; Erkelens and Mebius 2017).”
Background
Recent advances in encapsulation of fat-soluble vitamins using polysaccharides, proteins, and lipids: A review on delivery systems, formulation, and industrial applications.
Wijekoon, M. M. J. O., Mahmood, K., Ariffin, F., Nafchi, A. M., & Zulkurnain, M. (2023) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2023.124539 · Cited by 65 · see citing works
Gut microbiota supports male reproduction via nutrition, immunity, and signaling
Cai, H., Cao, X.-H., Qin, D., Liu, Y.-D., Liu, Y., Hua, J., & Peng, S. (2022) · Frontiers in Microbiology · doi:10.3389/fmicb.2022.977574 · Cited by 65 · see citing works
“Vitamin A deficiency leads to the failure of type A spermatogonial stem cells differentiation into type A1; the stratified squamous keratinizing epithelium replaces epithelia of the prostate, epididymis, and seminal vesicle, slowing sperm production (Clagett-Dame and Knutson, 2011).”
Background
Micronutrient composition and acceptability of Moringa oleifera leaf‐fortified dishes by children in Ada‐East district, Ghana
Glover‐Amengor, M., Aryeetey, R., Afari, E., & Nyarko, A. (2016) · Food Science & Nutrition · doi:10.1002/fsn3.395 · Cited by 64 · see citing works
A Clinician’s Guide to Topical Retinoids
Motamedi, M., Chehade, A., Sanghera, R., & Grewal, P. S. (2021) · Journal of Cutaneous Medicine and Surgery · doi:10.1177/12034754211035091 · Cited by 60 · see citing works
Effects of micronutrients on placental function: evidence from clinical studies to animal models.
Baker, B., Hayes, D., & Jones, R. L. (2018) · Reproduction · doi:10.1530/rep-18-0130 · Cited by 60 · see citing works
“Hypervitaminosis A results in congenital malformations, due to wide-ranging developmental actions, including axial polarisation and cell morphogenesis (Clagett-Dame & Knutson 2011).”
Background
Transport of vitamin A across blood‐tissue barriers is facilitated by STRA6
Kelly, M., Widjaja‐Adhi, M. A. K., Palczewski, G., & von Lintig, J. (2016) · The FASEB Journal · doi:10.1096/fj.201600446r · Cited by 60 · see citing works
The Biological Role of Vitamins in Athletes’ Muscle, Heart and Microbiota
Brancaccio, M., Mennitti, C., Cesaro, A., Fimiani, F., Vano, M., Gargiulo, B., Caiazza, M., Amodio, F., Coto, I., D’Alicandro, G., et al. (2022) · International Journal of Environmental Research and Public Health · doi:10.3390/ijerph19031249 · Cited by 66 · see citing works
An Updated Comprehensive Review on Vitamin A and Carotenoids in Breast Cancer: Mechanisms, Genetics, Assessment, Current Evidence, and Future Clinical Implications
Kim, J. A., Jang, J., & Lee, S. (2021) · Nutrients · doi:10.3390/nu13093162 · Cited by 66 · see citing works
“Recently, there have been study results indicating that vitamin A is required for the formation of the reproduction system in both males and females [61].”
Background
Retinoic acid signaling in ovarian folliculogenesis and steroidogenesis
Damdimopoulou, P., Chiang, C., & Flaws, J. (2019) · Reproductive Toxicology · doi:10.1016/j.reprotox.2019.04.007 · Cited by 56
A ζ-carotene desaturase gene, IbZDS , increases β-carotene and lutein contents and enhances salt tolerance in transgenic sweetpotato
Li, R., Kang, C., Song, X., Yu, L., Liu, D., He, S., Zhai, H., & Liu, Q. (2017) · Plant Science · doi:10.1016/j.plantsci.2017.05.014 · Cited by 64 · see citing works
The hydatidiform mole
Candelier, J. (2016) · Cell Adhesion & Migration · doi:10.1080/19336918.2015.1093275 · Cited by 56
Retinoic acid promotes Sertoli cell differentiation and antagonises activin-induced proliferation.
Nicholls, P. K., Harrison, C., Rainczuk, K., Vogl, A., & Stanton, P. G. (2013) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2013.06.034 · Cited by 55
Obesity and male fertility disorders
Cannarella, R., Crafa, A., Curto, R., Condorelli, R. A., Vignera, S. L., & Calogero, A. E. (2024) · Molecular Aspects of Medicine · doi:10.1016/j.mam.2024.101273 · Cited by 53 · see citing works
The molecular aspects of absorption and metabolism of carotenoids and retinoids in vertebrates
Widjaja‐Adhi, M. A. K., & Golczak, M. (2019) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/j.bbalip.2019.158571 · Cited by 65 · see citing works
“It is impossible to overestimate the significance of this regulatory molecule for the physiology and pathophysiology of vertebrates as it is involved in the transcriptional regulation of over 500 different genes [5, 156-159].”
Background
Vitamin A and the eye: an old tale for modern times.
Faustino, J., Ribeiro-Silva, A., Dalto, R. F., de Souza, M. M., Furtado, J. M., Rocha, G. D. M., Alves, M., & Rocha, E. (2016) · Arquivos Brasileiros de Oftalmologia · doi:10.5935/0004-2749.20160018 · Cited by 51 · see citing works
Role of Vitamin A in Mammary Gland Development and Lactation
Cabezuelo, M. T., Zaragozá, R., Barber, T., & Vinã, J. R. (2019) · Nutrients · doi:10.3390/nu12010080 · Cited by 64 · see citing works
Role of Milk Micronutrients in Human Health
Cimmino, F., Catapano, A., Petrella, L., Villano, I., Tudisco, R., & Cavaliere, G. (2023) · Frontiers in Bioscience-Landmark · doi:10.31083/j.fbl2802041 · Cited by 52 · see citing works
“It also sustains fetal development and embryonic growth [95].”
Background
All-trans Retinoic Acid as a Versatile Cytosolic Signal Modulator Mediated by CRABP1
Nagpal, I., & Wei, L. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20153610 · Cited by 51 · see citing works
“For cells that do not generate RA, they can obtain RA from RA-producing neighboring cells as a paracrine or from circulation as an endocrine factor [54].”
Background
Vitamin A Deficiency Induces Autistic‐Like Behaviors in Rats by Regulating the RARβ‐CD38‐Oxytocin Axis in the Hypothalamus
Lai, X., Wu, X., Hou, N., Liu, S., Li, Q., Yang, T., Miao, J., Dong, Z., Chen, J., & Li, T. (2017) · Molecular Nutrition & Food Research · doi:10.1002/mnfr.201700754 · Cited by 51 · see citing works
“As one of the important micronutrients for growth and development, VA has multiple physiological functions during embryonic development [39] .”
Background
Poly (ADP-ribose) glycohydrolase regulates retinoic acid receptor-mediated gene expression.
May, N. L., Iltis, I., Amé, J., Zhovmer, A., Biard, D., Egly, J., Schreiber, V., & Coin, F. (2012) · Molecules and Cells · doi:10.1016/j.molcel.2012.09.021 · Cited by 48 · see citing works
“The all-trans retinoic acid (t-RA), the ligand of RAR, is a pleiotropic signaling molecule derived from vitamin A that regulates critical genetic programs, thereby controlling cell proliferation and differentiation, as well as cell death or survival (Clagett-Dame and Knutson, 2011).”
Background
From in planta Function to Vitamin-Rich Food Crops: The ACE of Biofortification
Strobbe, S., Lepeleire, J. D., & Straeten, D. V. D. (2018) · Frontiers in Plant Science · doi:10.3389/fpls.2018.01862 · Cited by 53 · see citing works
Vitamin A prevents round spermatid nuclear damage and promotes the production of motile sperm during in vitro maturation of vitrified pre-pubertal mouse testicular tissue.
Dumont, L., Oblette, A., Rondanino, C., Jumeau, F., Bironneau, A., Liot, D., Duchesne, V., Wils, J., & Rives, N. (2016) · Molecular human reproduction · doi:10.1093/molehr/gaw063 · Cited by 47
Vitamin A, endocrine tissues and hormones: interplay and interactions
Brossaud, J., Pallet, V., & Corcuff, J. (2017) · Endocrine Connections · doi:10.1530/ec-17-0101 · Cited by 43 · see citing works
“RA is a critical factor for the formation of the gonads in man and one of the major consequences of vitamin A deficiency apart from blindness is infertility (35, 76).”
Background
Synergistic activation of steroidogenic acute regulatory protein expression and steroid biosynthesis by retinoids: involvement of cAMP/PKA signaling.
Manna, P., Słominski, A., King, S., Stetson, C., & Stocco, D. (2014) · Endocrinology · doi:10.1210/en.2013-1694 · Cited by 45 · see citing works
Derivation of male germ cells from ram bone marrow mesenchymal stem cells by three different methods and evaluation of their fate after transplantation into the testis
Ghasemzadeh-Hasankolaei, M., Eslaminejad, M., & Sedighi-Gilani, M. (2015) · In Vitro Cellular & Developmental Biology - Animal · doi:10.1007/s11626-015-9945-4 · Cited by 44 · see citing works
“Their undeniable functions in cell proliferation, differentiation and apoptosis, reproductive competence, GC production, and triggering GC meiosis and gametogenesis have been described (Bowles and Koopman 2007; Clagett-Dame and Knutson 2011; Gudas and Wagner 2011).”
Background
Insights into retinoic acid deficiency and the induction of craniofacial malformations and microcephaly in fetal alcohol spectrum disorder
Petrelli, B., Bendelac-Kapon, L., Hicks, G. G., & Fainsod, A. (2019) · genesis · doi:10.1002/dvg.23278 · Cited by 51 · see citing works
“Deviations from the nor- mal physiological condition can result in severe developmental malfor- mations (Adams, 2010; Campo-Paysaa, Marlétaz, Laudet, & Schubert, 2008; Clagett-Dame & Knutson, 2011; Kedishvili, 2013; Mark, Ghyse- linck, & Chambon, 2009).”
Input overload: contributions of retinoic acid signaling feedback mechanisms to heart development and teratogenesis
D'Aniello, E., & Waxman, J. (2015) · Developmental Dynamics · doi:10.1002/dvdy.24232 · Cited by 43 · see citing works
“…et al., 2006; Pan and Baker, 2007; Duester, 2008; Niederreither and Dolle, 2008; Pares et al., 2008; Mark et al., 2009; Pennimpede et al., 2010; Clagett-Dame and Knutson, 2011; Rhinn and Dolle, 2012; Samarut and RochetteEgly, 2012; Schilling et al., 2012; Duester, 2013; Kedishvili, 2013; Das…”
Background
RARγ is Essential for Retinoic Acid Induced Chromatin Remodeling and Transcriptional Activation in Embryonic Stem Cells
Kashyap, V., Laursen, K. B., Brenet, F. A., Viale, A. J., Scandura, J. M., & Gudas, L. J. (2012) · Journal of Cell Science · doi:10.1242/jcs.119701 · Cited by 68 · see citing works
Nutrition, genetic variation and male fertility
Vanderhout, S. M., Panah, M. R., García‐Bailo, B., Grace-Farfaglia, P., Samsel, K., Dockray, J., Jarvi, K. A., & El‐Sohemy, A. (2021) · Translational Andrology and Urology · doi:10.21037/tau-20-592 · Cited by 54 · see citing works
“Vitamin A deficiency damages the seminiferous epithelium of the epididymis, prostate, and the seminal vesicle, which results in the termination of spermatogenesis (71).”
Background
Alterations in retinoic acid signaling affect the development of the mouse coronary vasculature
Wang, S., Huang, W., Castillo, H. A., Kane, M. A., Xavier‐Neto, J., Trainor, P. A., & Moise, A. R. (2018) · Developmental Dynamics · doi:10.1002/dvdy.24639 · Cited by 43 · see citing works
“Retinoic acid (RA), an active metabolite of vitamin A, carries out regulatory roles in many essential processes during both embryonic and postembryonic life (Clagett-Dame and Knutson, 2011).”
Background
Retinoic Acid signaling regulates Krt5 and Krt14 independently of stem cell markers in submandibular salivary gland epithelium
Abashev, T. M., Metzler, M. A., Wright, D., & Sandell, L. L. (2017) · Developmental Dynamics · doi:10.1002/dvdy.24476 · Cited by 42 · see citing works
“RA, the active metabolite of vitamin A (all-trans-retinol), is a small lipid soluble molecule that regulates many aspects of embryogenesis and adult health (reviewed in Clagett-Dame and Knutson, 2011).”
Background
The all-trans retinoic acid (atRA)-regulated gene Calmin (Clmn) regulates cell cycle exit and neurite outgrowth in murine neuroblastoma (Neuro2a) cells
Marzinke, M. A., & Clagett-Dame, M. (2012) · Experimental Cell Research · doi:10.1016/j.yexcr.2011.10.002 · Cited by 42 · see citing works
Self-citation
The Expanding Role of Cancer Stem Cell Marker ALDH1A3 in Cancer and Beyond
McLean, M. E., MacLean, M. R., Cahill, H. F., Arun, R., Walker, O. L., Wasson, M., Fernando, W., Venkatesh, J., & Marcato, P. (2023) · Cancers · doi:10.3390/cancers15020492 · Cited by 41
“RA treatment can reduce the severity of asthma [18,19], while in contrast, retinoid and vitamin A deficiency exacerbate the condition [20,21].”
Background
Up-regulation of steroid biosynthesis by retinoid signaling: Implications for aging
Manna, P., Stetson, C., Daugherty, C., Shimizu, I., Syapin, P., Garrel, G., Cohen-Tannoudji, J., Huhtaniemi, I., Słominski, A., Pruitt, K., et al. (2015) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2015.08.007 · Cited by 40 · see citing works
“Retinoids, the metabolically active structural derivatives of vitamin A, especially atRA and 9-cis RA, exert a wide range of effects on development, differentiation, reproduction and epidermal homeostasis (Clagett-Dame and Knutson, 2011; Inoue et al., 2012; Jacobs et al., 2006; Vernet et al., 2006).”
Influential
Binding interaction and stability of alpha-lactalbumin and retinol: Effects of pre- or post-acidification
Chen, W., Li, J.-Z., Ma, Y., Shi, R.-J., Yu, H.-Y., Gantumur, M.-A., Bilawal, A., & Jiang, Z.-M. (2022) · Food Hydrocolloids · doi:10.1016/j.foodhyd.2022.108140 · Cited by 38
Modulation of retinoid signaling: therapeutic opportunities in organ fibrosis and repair
Wang, S., Yu, J., Kane, M. A., & Moise, A. R. (2019) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2019.107415 · Cited by 43 · see citing works
Cosmetic retinoid use in photoaged skin: A review of the compounds, their use and mechanisms of action
Mambwe, B., Mellody, K. T., Kiss, O., O’Connor, C., Bell, M., Watson, R. E. B., & Langton, A. K. (2024) · International Journal of Cosmetic Science · doi:10.1111/ics.13013 · Cited by 37 · see citing works
Vitamin A Deficiency Induces Congenital Spinal Deformities in Rats
Li, Z., Shen, J.-X., Wu, W., Wang, X., Liang, J.-Q., Qiu, G., & Liu, J.-M. (2012) · PLoS ONE · doi:10.1371/journal.pone.0046565 · Cited by 37 · see citing works
“Nervous system, cardiovascular, and axial patterning defects may be caused by early VAD, whereas a less well-developed nasal region, salivary gland hypoplasia, agenesis of the Harderian glands, hypoplasia of the intestinal villi and a number of skeleton abnormalities arise if VAD occurs at later times [22].”
BackgroundResult
Effects of nutrition and gestational alcohol consumption on fetal growth and development
Naik, V. D., Lee, J., Wu, G.-Y., Washburn, S. E., & Ramadoss, J. (2022) · Nutrition reviews · doi:10.1093/nutrit/nuab119 · Cited by 36
Danio rerio embryos on Prozac - Effects on the detoxification mechanism and embryo development.
Cunha, V., Rodrigues, P., Santos, M. M., Moradas-Ferreira, P., & Ferreira, M. (2016) · Aquatic Toxicology · doi:10.1016/j.aquatox.2016.08.003 · Cited by 36
“…RXR), play an important role in embryonic development, since both an excess and a deﬁciency of vitamin A can lead to a wide range of abnormalities in the developing embryos (Klymkowsky et al., 2010; Clagett-Dame and Knutson, 2011; André et al., 2014; Xavier-Neto et al., 2015; Samarut et al., 2015).”
Background
The lycopene β-cyclase plays a significant role in provitamin A biosynthesis in wheat endosperm
Zeng, J., Wang, C., Chen, X., Zang, M., Yuan, C., Wang, X., Wang, Q., Li, M., Li, X., Chen, L., et al. (2015) · BMC Plant Biology · doi:10.1186/s12870-015-0514-5 · Cited by 35 · see citing works
“Given the huge daily consumption of wheat-based products in populations worldwide, increasing the β-carotene content in wheat grains could significantly impact VAD.”
BackgroundInfluential
A critical role for the retinoic acid signaling pathway in the pathophysiology of gastrointestinal graft-versus-host disease.
Chen, X., Dodge, J., Komorowski, R., & Drobyski, W. (2012) · Blood · doi:10.1182/blood-2012-08-445130 · Cited by 35
“RA is an active metabolite of vitamin A that is involved in many important biological processes in vivo.(12,13) Within the immune system, RA influences many immune cell lineages and regulates an array of immune responses.”
Background
Regulation of retinoid mediated cholesterol efflux involves liver X receptor activation in mouse macrophages.
Manna, P., Sennoune, S., Martínez‐Zaguilán, R., Słominski, A., & Pruitt, K. (2015) · Biochemical and Biophysical Research Communications - BBRC · doi:10.1016/j.bbrc.2015.06.150 · Cited by 34 · see citing works
All-trans retinoic acid improves goat oocyte nuclear maturation and reduces apoptotic cumulus cells during in vitro maturation.
Pu, Y., Wang, Z.-F., Bian, Y.-N., Zhang, F., Yang, P., Li, Y.-S., Zhang, Y.-H., Liu, Y., Fang, F., Cao, H.-G., et al. (2014) · Animal science journal = Nihon chikusan Gakkaiho · doi:10.1111/asj.12216 · Cited by 34 · see citing works
Regulation of germ cell meiosis in the fetal ovary.
Spiller, C. M., Bowles, J., & Koopman, P. (2012) · International Journal of Developmental Biology · doi:10.1387/ijdb.120142pk · Cited by 34 · see citing works
Vitamin A Requirements in Pregnancy and Lactation
Gannon, B. M., Jones, C., & Mehta, S. (2020) · Current Developments in Nutrition · doi:10.1093/cdn/nzaa142 · Cited by 33 · see citing works
“Hypervitaminosis A has also led to altered placental morphology and agenesis (154), as well as fetal congenital malformations (15, 17).”
Background
Biological Roles of Lipocalins in Chemical Communication, Reproduction, and Regulation of Microbiota
Stopková, R., Otcenásková, T., Matějková, T., Kuntová, B., & Stopka, P. (2021) · Frontiers in Physiology · doi:10.3389/fphys.2021.740006 · Cited by 33 · see citing works
Comparison of carrying mechanism between three fat-soluble vitamins and alpha-lactalbumin: Effects on structure and physicochemical properties of alpha-lactalbumin
Chen, W., Yu, H.-Y., Shi, R.-J., Ma, C., Gantumur, M.-A., Qayum, A., Bilawal, A., Liang, G.-Z., Oh, K.-C., Jiang, Z.-M., et al. (2021) · Food Hydrocolloids · doi:10.1016/j.foodhyd.2021.106662 · Cited by 33
The retinoic acid hydroxylase Cyp26a1 has minor effects on postnatal vitamin A homeostasis, but is required for exogenous atRA clearance
Zhong, G. G., Hogarth, C. A., Snyder, J. M., Palau, L., Topping, T., Huang, W., Czuba, L. C., LaFrance, J., Ghiaur, G., & Isoherranen, N. (2019) · Journal of Biological Chemistry · doi:10.1074/jbc.ra119.009023 · Cited by 33 · see citing works
“5 (4) Cyp26a1 / 440 153 (4) 267 110 (4) 182 92 (4) 113 61 (3) 8.”
Metabolic disturbances of the vitamin A pathway in human diaphragmatic hernia.
Coste, K., Beurskens, L., Blanc, P., Gallot, D., Delabaere, A., Blanchon, L., Tibboel, D., Labbé, A., Rottier, R., & Sapin, V. (2015) · American Journal of Physiology - Lung cellular and Molecular Physiology · doi:10.1152/ajplung.00108.2014 · Cited by 33 · see citing works
“2) The phenotype of the RAR alpha/beta knockout mice recapitulates most of the lung defects observed in VAD animal models (6, 26).”
Background
Cutaneous Retinoic Acid Levels Determine Hair Follicle Development and Downgrowth*
Okano, J., Lévy, C., Lichti, U., Sun, H.-W., Yuspa, S., Sakai, Y., & Morasso, M. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.397273 · Cited by 33 · see citing works
The Impact of Preconceptional Multiple-Micronutrient Supplementation on Female Fertility
Schaefer, E., & Nock, D. (2019) · Clinical Medicine Insights: Women's Health · doi:10.1177/1179562x19843868 · Cited by 32 · see citing works
Retinoic acid receptor signaling is necessary in steroidogenic cells for normal spermatogenesis and epididymal function
Jauregui, E. J., Mitchell, D., Topping, T., Hogarth, C., & Griswold, M. (2018) · Development · doi:10.1242/dev.160465 · Cited by 32 · see citing works
“…for spermatogonial differentiation, meiotic initiation, the formation of BTB, spermiogenesis and spermiation (Huang and Hembree, 1979; Griswold et al., 1989; Chung and Wolgemuth, 2004; Wolgemuth and Chung, 2007; Clagett-Dame and Knutson, 2011; Hogarth et al., 2011; Raverdeau et al., 2012).”
Background
Vitamin A, D, E, and K as Matrix Metalloproteinase-2/9 Regulators That Affect Expression and Enzymatic Activity
Vo, H. V. T., Nguyen, Y. T., Kim, N., & Lee, H. J. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms242317038 · Cited by 31 · see citing works
“They are involved in different activities including vision, immunity, cell differentiation, embryological development, cellular differentiation and proliferation and antioxidant functions [4,85].”
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Breeding peppers for industrial uses: Progress and prospects
Barik, S., Ponnam, N., Reddy, A. C., Lakshmana Reddy, D. C., Saha, K., C, A. G., & Madhavi Reddy, K. (2022) · Industrial Crops and Products · doi:10.1016/j.indcrop.2022.114626 · Cited by 44 · see citing works
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A human induced pluripotent stem cell-based in vitro assay predicts developmental toxicity through a retinoic acid receptor-mediated pathway for a series of related retinoid analogues.
Palmer, J., Smith, A. M., Egnash, L. A., Colwell, M. R., Donley, E., Kirchner, F., & Burrier, R. (2017) · Reproductive Toxicology · doi:10.1016/j.reprotox.2017.07.011 · Cited by 31
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“[7] Infertility and its associated problems are important issues in the couple lives and sperm dysfunction is a major cause of infertility in men.[8] About 40% of infertility problems are associated with men.”
Background
β-Apo-10′-carotenoids Modulate Placental Microsomal Triglyceride Transfer Protein Expression and Function to Optimize Transport of Intact β-Carotene to the Embryo*
Costabile, B. K., Kim, Y.-K., Iqbal, J., Zuccaro, M., Wassef, L., Narayanasamy, S., Curley, R. W., Harrison, E., Hussain, M., & Quadro, L. (2016) · Journal of Biological Chemistry · doi:10.1074/jbc.m116.738336 · Cited by 30 · see citing works
“The importance of vitamin A as a critical modulator of mammalian embryonic development has been known for decades (1).”
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Retinoid signaling controls spermatogonial differentiation by regulating expression of replication-dependent core histone genes
Chen, Y., Ma, L., Hogarth, C., Wei, G., Griswold, M., & Tong, M.-H. (2016) · Development · doi:10.1242/dev.135939 · Cited by 30 · see citing works
“One of the major biological functions of RA is to inhibit cell proliferation (Bohnsack and Hirschi, 2004; Clagett-Dame and Knutson, 2011); however, RA is capable of stimulating cell proliferation in some type of cells such as neural crest-derived mesenchyme in the forebrain (Schneider et al., 2001)…”
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Environmental aspects of congenital scoliosis
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“…the requirement for vitamin A begins with embryonic life as noted by early nutritionists who reported that maternal insufficiency of vitamin A during pregnancy resulted in fetal death or congenital abnormalities in the offspring (Clagett-Dame and Knutson 2011; Lelievre-Pegorier et al. 1998).”
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Modulatory role of vitamin A on the Candida albicans-induced immune response in human monocytes
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“In this form, vitamin A is known to play an essential role in multiple biological processes, including reproduction, embryogenesis, maintenance of body tissues and augmentation of the immune sys-tem [6–8].”
Background
Juvenile hormones direct primordial germ cell migration to the embryonic gonad
Barton, L., Sanny, J. S. P., Dawson, E. P., Nouzová, M., Noriega, F. G., Stadtfeld, M., & Lehmann, R. (2024) · Current Biology · doi:10.1016/j.cub.2023.12.033 · Cited by 29 · see citing works

Authors: Clagett-Dame, M., & Knutson, D.
Affiliations: Department of Biochemistry, University of Wisconsin-Madison, 433 Babcock Drive, Madison, WI 53706, USA
University of Wisconsin–Madison (US)
Venue: Nutrients
Publisher: MDPI AG
Published: 2011-03-29
Volume: 3
Issue: 4
Pages: 385-428
ISSN: 2072-6643 (ISSN-L)
DOI: 10.3390/nu3040385
PMC: PMC3257687
OpenAlex: W2068902736
Cited by: 439
References: 309
Citations by year: 2026: 27 · 2025: 28 · 2024: 43 · 2023: 46 · 2022: 25 · 2021: 31 · 2020: 36 · 2019: 34 · 2018: 24 · 2017: 24 · 2016: 26 · 2015: 28 · 2014: 28 · 2013: 18 · 2012: 18
FWCI: 1.94
Type: journal article
Language: en
Open access: gold
doi.org
Licence: cc-by
creativecommons.org/licenses/by/3.0/ (vor)
Locations: Nutrients (publishedVersion, cc-by)
Europe PMC (PubMed Central) (publishedVersion, cc-by)
PubMed Central (publishedVersion, cc-by)
PubMed (publishedVersion)
DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders: National Institutes of Health (5p01dk014881-28)
National Cancer Institute (CA49837, R01CA049837)
National Institute of Diabetes and Digestive and Kidney Diseases (DK-14881, T32-DK-07665, T32DK007665)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinoids in leukemia and cellular processes
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinal Development and Disorders
Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Birth, Development, and Health
Keywords: vitamin A, all-trans retinoic acid, reproduction, embryonic development, vitamin A deficiency, retinoic acid receptor, spermatogenesis, male genital tract, meiosis initiation, organogenesis, carotene
MeSH terms: Retinoic Acid 4-Hydroxylase, Animals, Cytochrome P-450 Enzyme System, Diet, Eye, Female, Infertility, Male, Maternal-Fetal Exchange, Oocytes, Ovary, Pregnancy, Reproduction, Spermatogenesis, Vitamin A, Vitamin A Deficiency, Organogenesis, Embryonic Development, Rats

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Vitamin A in Reproduction and Development

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