The Function of Vitamin A in Cellular Growth and Differentiation, and Its Roles during Pregnancy and Lactation

  • A. Catharine Ross
  • Elizabeth M. Gardner
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 352)


In 1913, vitamin A was first described as a nutritional factor essential for growth and life itself, but another 18 years passed before the chemical nature of vitamin A was elucidated (see Ross, 1991). The term vitamin A is now used to comprise retinol and the retinol precursor, β-carotene, as well as the natural metabolites of retinol which retain growth- and health-promoting activities. A principal active metabolite of vitamin A is retinoic acid, formed in cells through the regulated oxidation of retinol. The term “retinoids” was coined to include both the natural forms of vitamin A and an expanding array of synthetic analogs which bear a structural relationship to retinol or retinoic acid and which generally share some but not all of their biological properties (Sporn and Roberts, 1985; De Luca, 1991; Frickel, 1984).


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Boylan, J. F. and Gudas, L. J., 1991, Overexpression of the cellular retinoic acid binding protein-I (CRABP-I) results in a reduction in differentiation-specific gene expression in F9 teratocarcinoma cells, J. Cell Biol. 112:965.PubMedCrossRefGoogle Scholar
  2. Chytil, F. and ul-Haq, R., 1990, Vitamin A mediated gene expression, Crit. Rev. Eukar. Gene Expr. 1:61.Google Scholar
  3. Dann, W. J., 1932, The transmission of vitamin A from parents to young in mammals, Biochem. J. 26:1072.PubMedGoogle Scholar
  4. Davila, M. E., Norris, L., Cleary, M. P., and Ross, A. C., Vitamin A during lactation: relationship of maternal diet to milk vitamin A content and to the vitamin A status of lactating rats and their pups, J. Nutr. 115:1033.Google Scholar
  5. DeLeeuw, A. M., Gaur, V. P., Saari, J. C., and Milam, A. H., 1990, Immunolocalization of cellular retinol-, retinaldehyde-and retinoic acid-binding proteins in rat retina during pre-and postnatal development, J. Neurocytology 19:253.CrossRefGoogle Scholar
  6. De Luca, L. M., 1991, Retinoids and their receptors in differentiation, embryogenesis, and neoplasia, FASEB J. 5:2924.PubMedGoogle Scholar
  7. Dollé, P., Ruberte, E., Kastner, P., Petkovich, M., Stoner, C. M., Gudas, L. J., and Chambon, P., 1989, Differential expression of genes encoding alpha, beta, and gamma retinoic acid receptors and CRABP in the developing limbs of the mouse, Nature 342:702.PubMedCrossRefGoogle Scholar
  8. Eichele, G., 1989, Retinoids and vertebrate limb pattern formation, TIG 5:246.PubMedCrossRefGoogle Scholar
  9. Eichele, G., Tickle, C., and Alberts, B. M., 1985, Studies on the mechanism of retinoid-induced pattern duplications in the early chick limb bud: temporal and spatial aspects, J. Cell Biol. 101:1913.PubMedCrossRefGoogle Scholar
  10. Evans, R. M., 1988, The steroid and thyroid hormone receptor superfamily, Science 240:889.PubMedCrossRefGoogle Scholar
  11. Frickel, F., 1984, Chemistry and physical properties of retinoids, in “The Retinoids, vol. 1”, M. B. Sporn, A. B. Roberts, and D. S. Goodman, eds., Academic Press, Inc., Orlando, FL.Google Scholar
  12. Giguère, V., Ong, E. S., Segui, P., and Evans, R. M., 1987, Identification of a receptor for the morphogen retinoic acid, Nature 330:624.PubMedCrossRefGoogle Scholar
  13. Glass, C. K., Devary, O. V., and Rosenfeld, M. G., Multiple cell type-specific proteins differentially regulate target sequence recognition by the a retinoic acid receptor, Cell 63:729.Google Scholar
  14. Hamosh, M., Clary, T. R., Chernick, S. S., and Scow, R. O., 1970, Lipoprotein lipase activity of adipose and mammary tissue and plasma triglyceride in pregnant and lactating rats, Biochim. Biophys. Acta 210:473.PubMedCrossRefGoogle Scholar
  15. Heyman, R. A., Mangelsdorf, D. J., Dyck, J. A., Stein, R. B., Eichele, G., Evans, R. M., and Thaller, C., 1992, 9-cis retinoic acid is a high affinity ligand for the retinoid X receptor, Cell 68:397.PubMedCrossRefGoogle Scholar
  16. Hoffmann, B., Lehmann, J. M., Zhang, X. K., Hermann, T., Husmann, M., Graupner, T., and Pfahl, M., 1990, A retinoic acid receptor-specific element controls the retinoic acid receptor-b promoter, Mol. Endocrinol. 4:1727.PubMedCrossRefGoogle Scholar
  17. Hrubetz, M. C., Deuel, H. J., Jr., and Hanley, B. J., 1945, Studies on carotenoid metabolism. V. The effect of a high vitamin A intake on the composition of human milk, J. Nutr. 29:245.Google Scholar
  18. Jessell, T. M., Ruiz, I., and Altaba, A., Retinoic acid modifies the pattern of cell differentiation in the central nervous system of neurula stage Xenopus embryos, Development 112:945.Google Scholar
  19. Kim, C. I., Leo, M. A., and Lieber C. S., 1992, Retinol forms retinoic acid via retinal, Arch. Biochem. Biophys. 294:388.PubMedCrossRefGoogle Scholar
  20. Kliewer, S. A., Umesono, K., Mangelsdorf, D. J., and Evans, R. M., 1992, Retinoid X receptor interacts with nuclear receptors in retinoic acid, thyroid hormone and vitamin D3 signalling, Nature 355:446.PubMedCrossRefGoogle Scholar
  21. Levin, A. A., Sturzenbecker, L. J., Kazmer, S., Bosakowski, T., Huselton, C., Allenby, G., Speck, J., Kratzeisen, C. L., Rosenberger, M., Lovey, A., and Grippo, J. F., 1992, 9-Cis retinoic acid stereoisomer binds and activates the nuclear receptor RXRa, Nature 355:359.PubMedCrossRefGoogle Scholar
  22. Maden, M., Hunt, P., Eriksson, U., Kuroiwa, A., Krumlauf, R., and Summerbell, D., 1991, Retinoic acid-binding protein, rhombomeres, and the neural crest, Development 111:35.PubMedGoogle Scholar
  23. Maden, M., Ong, D. E., Summerbell, D., and Chytil, F., 1988, Spatial distribution of cellular protein binding to retinoic acid in the chick limb bud, Nature 335:733.PubMedCrossRefGoogle Scholar
  24. Maden, M., and Summerbell, D., 1986, Retinoic acid-binding in the chick limb bud: identification at various developmental stages and binding affinities of various retinoids, J. Embryol. Exp. Morph. 97:239.PubMedGoogle Scholar
  25. Maden, M., Summerbell, D., Maignan, J., Darmon, M., and Shroot, B., 1991, The respecification of limb pattern by new synthetic retinoids and their interaction with cellular retinoic acid-binding protein, Diff. 47:49.CrossRefGoogle Scholar
  26. Makover, A., Soprano, D. R., Wyatt, M. L., and Goodman, D. S., 1989, An in situ-hybridization study of the localization of retinol-binding protein and transthyretin messenger RNAs during fetal development in the rat, Diff. 40:17.CrossRefGoogle Scholar
  27. Mangelsdorf, D. J., Borgmeyer, U., Heyman, R. A., Zhou, J. Y., Ong, E. S., Oro, A. E., Kakizuka, A., and Evans, R. M., 1992, Characterization of three RXR genes that mediate the action of 9-cis retinoic acid, Genes & Development 6:329.CrossRefGoogle Scholar
  28. Mangelsdorf, D. J., Ong, E. S., Dyck, J. A., and Evans, R. M., 1990, Nuclear receptor that identifies a novel retinoic acid response pathway, Nature 345:224.PubMedCrossRefGoogle Scholar
  29. Mangelsdorf, D. J., Umesono, K., Kliewer, S. A., Borgmeyer, U., Ong, E. S., and Evans, R. M., 1991, A direct repeat in the cellular retinol-binding protein type II gene confers differential regulation by RXR and RAR, Cell 66:555.PubMedCrossRefGoogle Scholar
  30. Mason, K. E., 1935, Foetal death, prolonged gestation and difficult parturition in the rat as a result of vitamin A deficiency, Amer. J. Anat. 57:303.CrossRefGoogle Scholar
  31. Moore, T., 1971, Vitamin A transfer from mother to offspring in mice and rats, Internat J. Vit. Nutr. Res. 41:301.Google Scholar
  32. Napoli, J. L., Posch, K. P., Fiorella, P. D., and Boerman, M. H. E. M., 1991, Physiological occurrence, biosynthesis and metabolism of retinoic acid: evidence for roles of cellular retinol-binding protein (CRBP) and cellular retinoic acid-binding protein (CRABP) in the pathway of retinoic acid homeostasis, Biomed. & Pharmacother. 45:131.CrossRefGoogle Scholar
  33. Ong, D.E., 1984, A novel retinol binding protein from rat: purification and partial characterization, J. Biol. Chem. 262:1476.Google Scholar
  34. Ong, D. E., and Chytil, F., 1976, Changes in levels of cellular retinol-and retinoic-acid binding proteins of liver and lung during perinatal development of rat, Proc. Nat. Acad. Sci. USA 73:3976.PubMedCrossRefGoogle Scholar
  35. Ong, D. E., Lucas, P. C., Kakkad, B., and Quick, T. C., 1991, Ontogeny of two vitamin A-metabolizing enzymes and two retinol-binding proteins present in the small intestine of the rat, J. Lipid Res. 32:1521.PubMedGoogle Scholar
  36. Petkovich, M., Brand, N. J., Krust, A., and Chambon, P., 1987, A human retinoic acid receptor which belongs to the family of nuclear receptors, Nature 330:444.PubMedCrossRefGoogle Scholar
  37. Pfahl, M., Tzukerman, M., Zhang, X. K., Lehmann, J. M., Hermann, T., Wills, K. N., and Graupner, G., 1990, Nuclear retinoic acid receptors: cloning, analysis, and function, Meth. Enzymol. 189:256.PubMedCrossRefGoogle Scholar
  38. Posch, K. C., Boerman, M. H. E. M., Burns, R. D., and Napoli, J. L., 1991, Holocellular retinol binding protein as a substrate for microsomal retinal synthesis, Biochemistry 30:6224.PubMedCrossRefGoogle Scholar
  39. Randolph, R. K., Winkler, K. E., and Ross, A. C., Fatty acyl coA-dependent and-independent retinol esterification by rat liver and lactating mammary gland microsomes, Arch. Biochem. Biophys. 288:500.Google Scholar
  40. Roberts, A. B., and Sporn, M. B., 1984, Cellular biology and biochemistry of the retinoids, in “The Retinoids, vol. 2”, M. B. Sporn, A. B. Roberts, and D. S. Goodman, eds, Academic Press, Inc., Orlando, FL.Google Scholar
  41. Roberts, E. S., Vaz, A. D. N., and Coon, M. J., 1992, Role of isozymes of rabbit microsomal cytochrome P-450 in the metabolism of retinoic acid, retinol, and retinal, Mol. Pharm. 41:427.Google Scholar
  42. Ross, A. C., 1982, Retinol esterification by mammary gland microsomes from the lactating rat, J. Lipid Res. 23:133.PubMedGoogle Scholar
  43. Ross, A. C., 1991, Vitamin A: current understanding of the mechanisms of action, Nutrition Today 26:6.CrossRefGoogle Scholar
  44. Ross, A. C., 1993a, Overview of retinoid metabolism, J. Nutr. 123:346.PubMedGoogle Scholar
  45. Ross, A. C., 1993b, Cellular metabolism and activation of retinoids: roles of cellular retinoid-binding proteins, FASEB J. 7:317.PubMedGoogle Scholar
  46. Ross, A. C., Davila, M. E., and Cleary, M. P., 1985, Fatty acids and retinyl esters of rat milk: effects of diet and duration of lactation, J. Nutr. 115:1488.PubMedGoogle Scholar
  47. Rottman, J. N., Widom, R. L., Nadal-Ginard, B., Mahdavi, B., and Karathanasis, S. K., 1991, A retinoic acid-responsive element in the apolipoprotein AI gene distinguishes between two different retinoic acid response pathways, Mol. Cell Biol. 11:3814.PubMedGoogle Scholar
  48. Saunders, J. W., and Gasseling, M. T., 1968, Ecdodermal-mesenchymal interactions in the origin of limb symmetry, in “Epithelial-mesenchymal Interactions”, R. Fleischmajer, and R. E. Billingham, eds., Williams & Wilkins, Baltimore.Google Scholar
  49. Smith, S., and Eichele, G., 1991, Temporal and regional differences in the expression pattern of distinct retinoic acid receptor-b transcripts in the chick embryo, Development 111:245.PubMedGoogle Scholar
  50. Sobel, A. E., Rosenberg, A., and Kramer, B., 1950, Enrichment of milk vitamin A in normal lactating women, Am. J. Dis. Child. 80:932.Google Scholar
  51. Sommer, A., 1992, Vitamin A deficiency and childhood mortality, Lancet 339:864.CrossRefGoogle Scholar
  52. Soprano, D. R., Soprano, K. J., and Goodman, D. S., 1986, Retinol-binding protein and transthyretin mRNA levels in visceral yolk sac and liver during fetal development in the rat, Proc. Nat. Acad. Sci. USA 83:7330.PubMedCrossRefGoogle Scholar
  53. Soprano, D. R., Wyatt, M. L., Dixon, J. L., Soprano, K. J., and Goodman, D. S., 1988, Retinol-binding protein synthesis and secretion by the rat visceral yolk sac, J. Biol. Chem. 263:2934.PubMedGoogle Scholar
  54. Sporn, M. B., and Roberts, A. B., 1985, Introduction: what is a retinoid?, in “Retinoids, Differentiation, and Disease”, Pitman, London.Google Scholar
  55. Stolfus, R. J., Hakimi, M., Miller, K. W., and Rasmussen, K. M., 1992, High-dose vitamin A supplementation of lactating women in rural central Java, Indonesia improves mother’s and infant’s vitamin A status, FASEB J. 6:A1497 (abstract).Google Scholar
  56. Sucov, H. M., Murakami, K. K., and Evans, R. M., 1990, Characterization of an autoregulated response element in the mouse retinoic acid receptor b gene, Proc. Nat. Acad. Sci. USA 87:5392.PubMedCrossRefGoogle Scholar
  57. Summerbell, D., and Maden M., 1990, Retinoic acid, a developmental signalling molecule, TINS 13:142.PubMedGoogle Scholar
  58. Takahashi, Y. I., Smith, J. E., Winick, M., and Goodman, D. S., Vitamin A deficiency and fetal growth and development in the rat, J. Nutr. 105:1299.Google Scholar
  59. Takahashi, Y. I., Smith, J. E., and Goodman, D. S., 1977, Vitamin A and retinol-binding protein metabolism during fetal development in the rat, Am. J. Physiol. 233:E263.PubMedGoogle Scholar
  60. Thaller, C., and Eichele, G., 1987, Identification and spatial distribution of retinoids in the developing chick limb bud, Nature 327:625.PubMedCrossRefGoogle Scholar
  61. Thaller, C., and Eichele, G., 1988, Characterization of retinoid metabolism in the developing chick limb bud, Development 103:473.PubMedGoogle Scholar
  62. Thaller, C., and Eichele, G., 1990, Isolation of 3,4-didehydroretinoic acid, a novel morphogenetic signal in the chick wing bud, Nature 345:815.PubMedCrossRefGoogle Scholar
  63. Thompson, J. N., MacHowell, J., and Pitt, G. A. J., 1964, Vitamin A and reproduction in rats, Proc. R. Soc. Lond. Ser. B. 159:510.CrossRefGoogle Scholar
  64. Tickle, C., Alberts, L., Wolpert, L., and Lee, J., 1982, Local application of retinoic acid to the limb bud mimics the action of the zone of polarizing activity, Nature 296:564.PubMedCrossRefGoogle Scholar
  65. Tickle, C., Lee, J., and Eichele, G., 1985, A quantitative analysis of the effect of all-trans-retinoic acid on the pattern of chick wing development, Devel. Biol. 109:82.CrossRefGoogle Scholar
  66. Vahlquist, A., and Nilsson, S., 1979, Mechanisms for vitamin A transfer from blood to milk in rhesus monkeys, J. Nutr. 109:1456.PubMedGoogle Scholar
  67. Venkatachalam, P. S., Belavady, B., and Gopalan, C., 1962, Studies on vitamin A nutritional status of mothers and infants in poor communities of India, Trop. Ped. 61:262.Google Scholar
  68. Wagner, M. C., Thaller, C., Jessell, T., and Eichele, G., 1990, Polarizing activity and retinoid synthesis in the floor plate of the neural tube, Nature 345:818.CrossRefGoogle Scholar
  69. Wallingford, J. C., and Underwood, B. A., 1986, Vitamin A deficiency in pregnancy, lactation and the nursing child, in “Vitamin A Deficiency and its Control”, C. J. Bauernfield, ed., Academic Press, Inc., New York.Google Scholar
  70. Warkany, J., and Schraffenberger, E., 1945, Congenital malformations induced in rats by maternal vitamin A deficiency. I. Defects of the eye, Arch. Ophthalmol. 35:150.CrossRefGoogle Scholar
  71. Wilson, J. G., Roth, C. B., and Warkany, J., 1953, An analysis of the syndrome of malformations induced by maternal vitamin A deficiency. Effects of restoration of vitamin A at various times during gestation, Am. J. Anat. 92:189.PubMedCrossRefGoogle Scholar
  72. Wolbach, S. B., and Howe, P. R., 1925, Tissue changes following deprivation of fat-soluble A vitamin, J. Exp. Med. 42:753.PubMedCrossRefGoogle Scholar
  73. Wolf, G., 1990, Recent progress in vitamin A research: Nuclear retinoic acid receptors and their interaction with gene elements, J. Nutr. Biochem. 1:284.PubMedCrossRefGoogle Scholar
  74. Yang, N., Schüle, R., Mangelsdorf, D. J., and Evans, R. M., 1991, Characterization of DNA binding and retinoic acid binding properties of retinoic acid receptor, Proc. Nat. Acad. Sci. USA 88:3559.PubMedCrossRefGoogle Scholar
  75. Zachman, R. D., and Valceschini, G., 1988, Effects of premature delivery on rat lung retinol (vitamin A) and retinyl ester stores, Biol. Neonate 54:285.PubMedCrossRefGoogle Scholar
  76. Zhang, X-K., Hoffman, B., Tran, P. B-V., Graupner, G., and Pfahl, M., 1992, Retinoid X receptor is an auxiliary protein for thyroid hormone and retinoic acid receptors, Nature 355:441.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1994

Authors and Affiliations

  • A. Catharine Ross
    • 1
  • Elizabeth M. Gardner
    • 1
  1. 1.Division of Nutrition, Department of BiochemistryMedical College of PennsylvaniaPhiladelphiaUSA
  2. 2.Department of NutritionPenn State UniversityUniversity ParkUSA

Personalised recommendations