Hostname: page-component-cd9895bd7-lnqnp Total loading time: 0 Render date: 2024-12-26T16:24:28.890Z Has data issue: false hasContentIssue false
  • English
  • Français

The role of retinoic acid in embryonic and post-embryonic development

Published online by Cambridge University Press:  28 February 2007

Malcolm Maden
Malcolm Maden*
Affiliation:
The Randall Institute, King's College London, 26–29 Drury Lane, London WC2B 5RL, UK
*
*Corresponding author: Professor Malcolm Maden, fax +44 (0)207 497 9078, email [email protected]
Rights & Permissions [Opens in a new window]

Abstract

Core share and HTML view are not available for this content. However, as you have access to this content, a full PDF is available via the ‘Save PDF’ action button.

Retinoic acid (RA) is the bioactive metabolite of vitamin A (retinol) which acts on cells to establish or change the pattern of gene activity. Retinol is converted to RA by the action of two types of enzyme, retinol dehydrogenases and retinal dehydrogenases. In the nucleus RA acts as a ligand to activate two families of transcription factors, the RA receptors (RAR) and the retinoid X receptors (RXR) which heterodimerize and bind to the upstream sequences of RA-responsive genes. Thus, in addition to the well-established experimental paradigm of depriving animals of vitamin A to determine the role of RA in embryonic and post-embryonic development, molecular biology has provided us with two additional methodologies: knockout the enzymes or the RAR and RXR in the mouse embryo. The distribution of the enzymes and receptors, and recent experiments to determine the endogenous distribution of RA in the embryo are described here, as well as the effects on the embryo of knocking out the enzymes and receptors. In addition, recent studies using the classical vitamin A-deprivation technique are described, as they have provided novel insights into the regions of the embryo which crucially require RA, and the gene pathways involved in their development. Finally, the post-embryonic or regenerating systems in which RA plays a part are described, i.e. the regenerating limb, lung regeneration, hair cell regeneration in the ear and spinal cord regeneration in the adult.

Keywords

Retinoic acidRetinoidsDevelopmentRegeneration
Type
Micronutrient Group Symposium on ‘The role of micronutrients as modulators of development’
Information
Proceedings of the Nutrition Society , Volume 59 , Issue 1 , February 2000 , pp. 65 - 73
Copyright
Copyright © The Nutrition Society 2000

References

Abu-Abed, SS, Beckett, BR, Chiba, H, Chithalen, JV, Jones, G, Metzger, D, Chambon, P & Petkovich, M (1998) Mouse P450RAI (CYP26) expression and retinoic acid-inducible retinoic acid metabolism in F9 cells are regulated by retinoic acid receptor g and retinoid X receptor α. Journal of Biological Chemistry 273, 2409–2415.CrossRefGoogle Scholar
Ang, HL & Duester, G (1997) Initiation of retinoid signalling in primitive streak mouse embryos: spatiotemporal expression patterns of receptors and metabolic enzymes for ligand synthesis. Developmental Dynamics 208, 536–543.3.0.CO;2-J>CrossRefGoogle ScholarPubMed
Antipatis, C, Achworth, CJ, Grant, G, Lea, RG, Hay, SM & Rees, WD (1998) Effects of maternal vitamin A status on fetal heart and lung: changes in expression of key developmental genes. American Journal of Physiology 275, L1184–L1191.Google ScholarPubMed
Balkan, W, Colbert, M, Bock, C & Linney, E (1992) Transgenic indicator mice for studying activated retinoic acid receptors during development. Proceedings of the National Academy of Sciences USA 89, 3347–3351.CrossRefGoogle ScholarPubMed
Bavik, C, Ward, SJ & Ong, DE (1997) Identification of a mechanism to localize generation of retinoic acid in rat embryos. Mechanisms of Development 69, 155–167.CrossRefGoogle ScholarPubMed
Blomhoff, R (1994) Introduction: overview of vitamin A metabolism and function. In Vitamin A in Health and Disease, pp. 1–35 [Blomhoff, R, editor]. New York: Marcel Dekker Inc.CrossRefGoogle Scholar
Colbert, MC, Linney, E & LaMantia, AS (1993) Local sources of retinoic acid coincide with retinoid-mediated transgene activity during embryonic development. Proceedings of the National Academy of Sciences USA 90, 6572–6576.CrossRefGoogle ScholarPubMed
Costaridis, P, Horton, C, Zeitlinger, J, Holder, N & Maden, M (1996) Endogenous retinoids in the zebrafish embryo and adult. Developmental Dynamics 205, 41–51.3.0.CO;2-5>CrossRefGoogle ScholarPubMed
Creech-Kraft, J, Schuh, T, Juchau, MR & Kimelman, D (1994) Temporal distribution, localization and metabolism of all-trans-retinol, didehydroretinol and all-trans-retinal during Xenopus development. Biochemical Journal 301, 111–119.CrossRefGoogle ScholarPubMed
de Roos, K, Sonneveld, E, Compaan, B, ten, Berge D, Durston, AJ & van der, Saag PT (1999) Expression of retinoic acid 4-hydroxylase (CYP26) during mouse and Xenopus laevis embryogenesis. Mechanisms of Development 82, 205–211.CrossRefGoogle ScholarPubMed
Dersch, H & Zile, MH (1993) Induction of normal cardiovascular development in the vitamin A-deprived quail embryo by natural retinoids. Developmental Biology 160, 424–433.CrossRefGoogle ScholarPubMed
Dickman, ED, Thaller, C & Smith, SM (1997) Temporally-regulated retinoic acid depletion produces specific neural crest, ocular and nervous system defects. Development 124, 3111–3121.CrossRefGoogle ScholarPubMed
Dolle, P, Fraulob, V, Kastner, P & Chambon, P (1994) Developmental expression of murine retinoid X receptor (RXR) genes. Mechanisms of Development 45, 91–104.CrossRefGoogle ScholarPubMed
Dong, D & Zile, MH (1995) Endogenous retinoids in the early avian embryo. Biochemical and Biophysical Research Communications 217, 1026–1031.CrossRefGoogle ScholarPubMed
Duester, G (1996) Involvement of alcohol dehydrogenase, short-chain dehydrogenase/reductase, aldehyde dehydrogenase, and cytochrome P450 in the control of retinoid signalling by activation of retinoic acid synthesis. Biochemistry 35, 12221–12227.CrossRefGoogle ScholarPubMed
Durston, AJ, Timmermans, JPM, Hage, WJ, Hendricks, HFJ, de Vries, NJ, Heideveld, M & Nieuwkoop, PD (1989) Retinoic acid causes an anteroposterior transformation in the developing nervous system. Nature 340, 140–144.CrossRefGoogle Scholar
Fantel, AG, Shepard, TH, Newell-Morris, LL & Moffett, BC (1977) Teratogenic effects of retinoic acid in pigtail monkeys (Macaca nemestrina). Teratology 15, 65–72.CrossRefGoogle ScholarPubMed
Fujii, H, Sato, T, Kaneko, S, Gotoh, O, Fujii-Kuriyama, Y, Osawa, K, Kato, S & Hamada, H (1997) Metabolic inactivation of retinoic acid by a novel P450 differentially expressed in developing mouse embryos. EMBO Journal 16, 4163–4173.CrossRefGoogle ScholarPubMed
Godbout, R, Packer, M, Poppema, S & Dabbath, L (1996) Localization of cytosolic aldehyde dehydrogenase in the developing chick retina: in situ hydridisation and immunohistochemical analyses. Developmental Dynamics 205, 319–331.3.0.CO;2-#>CrossRefGoogle Scholar
Hale, F (1933) Pigs born without eye balls. Journal of Heredity 24, 105–106.CrossRefGoogle Scholar
Heine, UI, Roberts, AB, Munoz, EF, Roche, NS & Sporn, MB (1985) Effects of retinoid deficiency on the development of the heart and vascular system of the quail embryo. Cell Pathology 50, 135–152.Google ScholarPubMed
Hollemann, T, Chen, Y, Grunz, H & Pieler, T (1998) Regionalized metabolic activity establishes boundaries of retinoic acid signalling. EMBO Journal 17, 7361–7372.CrossRefGoogle ScholarPubMed
Horton, C & Maden, M (1995) Endogenous distribution of retinoids during normal development and teratogenesis in the mouse embryo. Developmental Dynamics 202, 312–323.CrossRefGoogle ScholarPubMed
Kalter, H & Warkany, J (1959) Experimental production of congenital malformations in mammals by metabolic procedure. Physiology Reviews 39, 69–115.CrossRefGoogle ScholarPubMed
Kastner, P, Chambon, P & Leid, M (1994a) Role of nuclear retinoic acid receptors in the regulation of gene expression. In Vitamin A in Health and Disease, pp. 189–238 [Blomhoff, R, editor]. New York: Marcel Dekker Inc.Google Scholar
Kastner, P, Grondona, JM, Mark, M, Gansmuller, A, LeMeur, M, Decimo, D, Vonesch, J-L, Dolle, P & Chambon, P (1994b) Genetic analysis of RXRa developmental function: convergence of RXR and RAR signalling pathways in heart and eye morphogenesis. Cell 78, 987–1003.CrossRefGoogle Scholar
Kastner, P, Mark, M & Chambon, P (1995) Nonsteroid nuclear receptors: what are genetic studies telling us about their role in real life? Cell 83, 859–869.CrossRefGoogle ScholarPubMed
Kastner, P, Mark, M, Ghyselinck, N, Krezel, W, Dupe, V, Grondona, JM & Chambon, P (1997) Genetic evidence that the retinoid signal is transduced by heterodimeric RXR/RAR functional units during mouse development. Development 124, 313–326.CrossRefGoogle ScholarPubMed
Kastner, P, Mark, M, Leid, M, Gansmuller, A, Chin, W, Grondona, JM, Decimo, D, Krezel, W, Dierich, A & Chambon, P (1996) Abnormal spermatogenesis in RXRb mutant mice. Genes and Development 10, 80–92.CrossRefGoogle Scholar
Kliewer, SA, Umesono, K, Evans, RM & Mangelsdorf, DJ (1994) The retinoid X receptors: modulators of multiple hormonal signaling pathways. In Vitamin A in Health and Disease, pp. 239–255 [Blomhoff, R, editor]. New York: Marcel Dekker Inc.Google Scholar
Knudsen, PA (1966) Congenital malformations of lower incisors and molars in exencephalic mouse embryos, induced by hypervitaminosis A. Acta Odontologica Scandinavica 24, 55–71.CrossRefGoogle Scholar
Kochhar, DM (1973) Limb development in mouse embryos. I. Analysis of teratogenic effects of retinoic acid. Teratology 7, 289–298.CrossRefGoogle ScholarPubMed
LaMantia, AS, Colbert, MC & Linney, E (1993) Retinoic acid induction and regional differentiation prefigure olfactory pathway formation in the mammalian forebrain. Neuron 10, 1035–1048.CrossRefGoogle ScholarPubMed
Lammer, EJ, Chen, DT, Hoar, RM, Agnish, AD, Benke, PJ, Braun, JT, Curry, CJ, Fernhoff, PM, Grix, AW, Lott, IT, Richard, JM & Sun, SC (1985) Retinoic acid embryopathy. New England Journal of Medicine 313, 837–841.CrossRefGoogle ScholarPubMed
Lefebvre, PP, Malgrange, B, Staecker, H, Moonen, G & de Water, TR (1993) Retinoic acid stimulates regeneration of mammalian auditory hair cells. Science 260, 692–695.CrossRefGoogle ScholarPubMed
Lohnes, D, Kastner, P, Dierich, A, Mark, M, LeMeur, M & Chambon, P (1993) Function of retinoic acid in the mouse. Cell 73, 643–658.CrossRefGoogle ScholarPubMed
Lufkin, T, Lohnes, D, Mark, M, Dierich, A, Gorry, P, Gaub, MP, LeMeur, M & Chambon, P (1993) High postnatal lethality and testis degeneration in retinoic acid receptor a mutant mice. Proceedings of the National Academy of Sciences USA 90, 7225–7229.CrossRefGoogle Scholar
McCaffery, P & Drager, UC (1994) Hot spots of retinoic acid synthesis in the developing spinal cord. Proceedings of the National Academy of Sciences USA 91, 7194–7197.CrossRefGoogle ScholarPubMed
McCaffery, P, Lee, M-O, Wagner, MA, Sladek, NE & Drager, U (1992) Asymmetrical retinoic acid synthesis in the dorsoventral axis of the retina. Development 115, 371–382.CrossRefGoogle ScholarPubMed
McCaffery, P, Posch, KC, Napoli, JL, Gudas, L & Drager, UC (1993) Changing patterns of the retinoic acid system in the developing retina. Developmental Biology 158, 390–399.CrossRefGoogle Scholar
McCaffery, P, Tempst, P, Lara, G & Drager, UC (1991) Aldehyde dehydrogenase is a positional marker in the retina. Development 112, 693–702.CrossRefGoogle ScholarPubMed
McCaffery, P, Wagner, E, O'Neil, J, Petkovich, M & Drager, UC (1999) Dorsal and ventral territories defined by retinoic acid synthesis, break-down and nuclear receptor expression. Mechanisms of Development 82, 119–130.CrossRefGoogle ScholarPubMed
Maden, M (1982) Vitamin A and pattern formation in the regenerating limb. Nature 295, 672–675.CrossRefGoogle ScholarPubMed
Maden, M (1983) The effect of vitamin A on limb regeneration in Rana temporaria. Developmental Biology 98, 409–416.CrossRefGoogle ScholarPubMed
Maden, M (1993) The homeotic transformation of tails into limbs in Rana temporaria by retinoids. Developmental Biology 159, 379–391.CrossRefGoogle ScholarPubMed
Maden, M (1998a) Retinoids as endogenous components of the regenerating limb and tail. Wound Repair and Regeneration 6, 358–365.CrossRefGoogle ScholarPubMed
Maden, M (1998b) Retinoids in neural development. In Retinoids, pp. 399–442 [Nau, H and Blaner, WS, editors]. Berlin: Springer-Verlag:.Google ScholarPubMed
Maden, M, Gale, E, Kostetskii, I & Zile, M (1996) Vitamin A-deficient quail embryos have half a hindbrain and other neural defects. Current Biology 6, 417–426.CrossRefGoogle ScholarPubMed
Maden, M, Gale, E & Zile, M (1998a) The role of vitamin A in the development of the central nervous system. Journal of Nutrition 128, 471S–475S.CrossRefGoogle ScholarPubMed
Maden, M, Sonneveld, E, van der, Saag PT & Gale, E (1998b) The distribution of endogenous retinoic acid in the chick embryo: implications for developmental mechanisms. Development 125, 4133–4144.CrossRefGoogle ScholarPubMed
Mangelsdorf, DJ, Borgmeyer, U, Heyman, RA, Khou, JY, Ong, ES, Oro, AE, Kakizuka, A & Evans, RM (1992) Characterisation of three RXR genes that mediate the action of 9-cis retinoic acid. Genes and Development 6, 329–344.CrossRefGoogle ScholarPubMed
Mascrez, B, Mark, M, Dierich, A, Ghyselinck, NB, Kastner, P & Chambon, P (1998) The RXRa ligand-dependent activation function 2 (AF02) is important for mouse development. Development 125, 4691–4707.CrossRefGoogle Scholar
Massaro, GDC & Massaro, D (1997) Retinoic acid treatment abrogates elastase-induced pulmonary emphysema in rats. Nature Medicine 3, 675–677.CrossRefGoogle ScholarPubMed
Mertz, JR, Shang, E, Piantedosi, R, Wei, S, Wolgemuth, DJ & Blaner, WS (1997) Identification and characterization of a stereospecific human enzyme that catalyses 9-cis-retinol oxidation. Journal of Biological Chemistry 272, 11744–11749.CrossRefGoogle Scholar
Mohanty-Hejmadi, P, Dutta, SK & Mahapatra, P (1992) Limbs generated at site of tail amputation in marbled balloon frog after vitamin A treatment. Nature 355, 352–353.CrossRefGoogle ScholarPubMed
Morriss-Kay, GM & Sokolova, N (1996) Embryonic development and pattern formation. FASEB Journal 10, 961–968.CrossRefGoogle ScholarPubMed
Moss, JB, Xavier-Neto, J, Shapiro, MD, Nayeem, SM, McCaffery, P, Drager, UC & Rosenthal, N (1998) Dynamic patterns of retinoic acid synthesis and response in the developing mammalian heart. Developmental Biology 199, 55–71.CrossRefGoogle ScholarPubMed
Muto, K, Noji, S, Nohno, T, Koyama, E, Myokai, F, Nishijima, K, Saito, T & Taniguchi, S (1991) Involvement of retinoic acid and its receptor b in differentiation of motoneurons in chick spinal cord. Neuroscience Letters 129, 39–42.CrossRefGoogle Scholar
Napoli, JL (1996) Retinoic acid biosynthesis and metabolism. FASEB Journal 10, 993–1001.CrossRefGoogle ScholarPubMed
Niazi, IA & Ratnasamy, CS (1984) Regeneration of whole limbs in toad tadpoles treated with retinol palmitate after the wound-healing stage. Journal of Experimental Zoology 230, 501–505.CrossRefGoogle Scholar
Niazi, IA & Saxena, S (1978) Abnormal hind limb regeneration in tadpoles of the toad, Bufo andersoni, exposed to excess vitamin A. Folia Biologica (Krakow) 26, 1–8.Google ScholarPubMed
Niederreither, K, McCaffery, P, Drager, UC, Chambon, P & Dolle, P (1997) Restricted expression and retinoic acid-induced downregulation of the retinaldehyde dehydrogenase type 2 (RALDH-2) gene during mouse development. Mechanisms of Development 62, 67–78.CrossRefGoogle ScholarPubMed
Niederreither, K, Subbarayan, V, Dolle, P & Chambon, P (1999) Embryonic retinoic acid synthesis is essential for early mouse post-implantation development. Nature Genetics 21, 444–448.CrossRefGoogle ScholarPubMed
Pecorino, L, Entwistle, A & Brockes, JP (1996) Activation of a single retinoic acid receptor isoform mediates proximodistal respecification. Current Biology 6, 563–569.CrossRefGoogle ScholarPubMed
Pecorino, LT, Lo, DC & Brockes, JP (1994) Isoform-specific induction of a retinoid-responsive antigen after biolistic transfection of chimaeric retinoic acid/thyroid hormone receptors into a regenerating limb. Development 120, 325–333.CrossRefGoogle ScholarPubMed
Pijnappel, WWM, Hendricks, HFJ, Folkers, GE, van den Brink, CE, Dekker, EJ, Edelenbosch, C, van der, Saag PT & Durston, AJ (1993) The retinoid ligand 4-oxo-retinoic acid is a highly active modulator of positional specification. Nature 366, 340–344.CrossRefGoogle ScholarPubMed
Ragsdale, CW, Gates, PB & Brockes, JP (1992a) Identification and expression pattern of a second isoform of the newt alpha retinoic acid receptor. Nucleic Acid Research 20, 5851.CrossRefGoogle ScholarPubMed
Ragsdale, CW, Gates, PB, Hill, DS & Brockes, JP (1992b) Delta retinoic acid receptor isoform d1 is distinguished by its exceptional N-terminal sequence and abundance in the limb regeneration blastema. Mechanisms of Development 40, 99–112.CrossRefGoogle Scholar
Ragsdale, CW, Petkovich, M, Gates, PB, Chambon, P & Brockes, JP (1989) Identification of a novel retinoic acid receptor in regenerating tissues of the newt. Nature 341, 654–657.CrossRefGoogle ScholarPubMed
Reynolds, K, Mezey, E & Zimmer, A (1991) Activity of the b-retinoic acid receptor promoter in transgenic mice. Mechanisms of Development 36, 15–29.CrossRefGoogle ScholarPubMed
Romert, A, Tuvendal, P, Simon, A, Dencker, L & Eriksson, U (1998) The identification of a 9-cis retinol dehydrogenase in the mouse embryo reveals a pathway for synthesis of 9-cis retinoic acid. Proceedings of the National Academy of Sciences USA 95, 4404–4409.CrossRefGoogle ScholarPubMed
Rosa, FW, Wilk, AL & Kelsey, FO (1986) Teratogen update: vitamin A congeners. Teratology 33, 355–364.CrossRefGoogle ScholarPubMed
Ross, CA & Hammerling, UG (1994) Retinoids and the immune system. In The Retinoids, pp. 521–543 [Sporn, MB, Roberts, AB and Goodman, DS, editors]. New York: Raven Press.Google Scholar
Rossant, J, Zirngibl, R, Cado, D, Shago, M & Giguere, V (1991) Expression of a retinoic acid response element-hsplacZ transgene defines specific domains of transcriptional activity during mouse embryogenesis. Genes and Development 5, 1333–1344.CrossRefGoogle ScholarPubMed
Ruberte, E, Dolle, P, Chambon, P & Morriss-Kay, G (1991) Retinoic acid receptors and cellular retinoid binding proteins. II Their differential pattern of transcription during early morphogenesis in mouse embryos. Development 111, 45–60.CrossRefGoogle ScholarPubMed
Ruberte, E, Dolle, P, Krust, A, Zebent, A, Morriss-Kay, G & Chambon, P (1990) Specific spatial and temporal distribution of retinoic acid receptor gamma transcripts during mouse embryogenesis. Development 108, 213–222.CrossRefGoogle ScholarPubMed
Ruberte, E, Friedrich, V, Chambon, P & Morriss-Kay, G (1993) Retinoic acid receptors and cellular retinoid binding proteins. III Their differential transcript distribution during mouse nervous system development. Development 118, 267–282.CrossRefGoogle ScholarPubMed
Satre, A & Kochhar, DM (1989) Elevations in the endogenous levels of the putative morphogen retinoic acid in embryonic mouse limb-buds associated with limb dysmorphogenesis. Developmental Biology 133, 529–536.CrossRefGoogle ScholarPubMed
Schilthuis, JG, Gann, AAF & Brockes, JP (1993) Chimeric retinoic acid/thyroid hormone receptors implicate RAR al as mediating growth inhibition by retinoic acid. EMBO Journal 12, 3459–3466.CrossRefGoogle Scholar
Scott, WJ, Walter, R, Tzimas, G, Sass, JO, Nau, H & Collins, MD (1994) Endogenous status of retinoids and their cytosolic binding proteins and limb buds of chick vs mouse embryos. Developmental Biology 165, 397–409.CrossRefGoogle ScholarPubMed
Shen, S, van den, Brink CE, Kruijer, W & van der, Saag PT (1992) Embryonic stem cells stably transfected with mRARb2-lacZ exhibit specific expression in chimeric embryos. International Journal of Developmental Biology 36, 465–476.Google ScholarPubMed
Shenfelt, RE (1972) Morphogenesis of malformations in hamsters caused by retinoic acid: relation to dose and stage at treatment. Teratology 5, 103–118.CrossRefGoogle Scholar
Sockanathan, S & Jessell, TM (1998) Motor neuron-derived retinoid signalling specifies the subtype identity of spinal motor neurons. Cell 94, 503–514.CrossRefGoogle ScholarPubMed
Sonneveld, E, van den, Brink CE, Tertoolen, LGJ, van der, Burg B & van der, Saag PT (1999) Retinoic acid hydroxylase (CYP26) is a key enzyme in neuronal differentiation of embryonal carcinoma cells. Developmental Biology 213, 390–404.CrossRefGoogle ScholarPubMed
Sucov, HM, Dyson, E, Gumeringer, CL, Price, J, Chien, KR & Evans, RM (1994) RXRa mutant mice establish a genetic basis for vitamin A signaling in heart morphogenesis. Genes and Development 8, 1007–1018.CrossRefGoogle Scholar
Thaller, C & Eichele, G (1990) Isolation of 3,4-didehydroretinoic acid, a novel morphogenetic signal in the chick wing bud. Nature 345, 815–819.CrossRefGoogle ScholarPubMed
Thompson, JN, Howell, JM, Pitt, GAJ & McLaughlin, CI (1969) The biological activity of retinoic acid in the domestic fowl and the effects of vitamin A deficiency on the chick embryo. British Journal of Nutrition 23, 471–490.CrossRefGoogle ScholarPubMed
Tyson, JE, Wright, LL, Oh, W, Kennedy, KA, Mele, L, Ehrenkranz, RA, Stoll, BJ, Lemons, JA, Stevenson, DK, Bauer, CR, Korones, SB & Faranoff, AA (1999) Vitamin A supplementation for extremely-low-birth-weight infants. National Institute of Child Health and Human Development Neonatal Research Network. New England Journal of Medicine 340, 1962–1968.CrossRefGoogle ScholarPubMed
Underwood, BA (1984) Vitamin A in animal and human nutrition. In The Retinoids, pp. 281–392 [Sporn, MB, Roberts, AB and Goodman, DS, editors]. New York: Academic Press.CrossRefGoogle Scholar
Viviano, CM, Horton, C, Maden, M & Brockes, JP (1995) Synthesis and release of 9-cis retinoic acid by the urodele wound epidermis. Development 121, 3753–3762.CrossRefGoogle Scholar
Vonesch, J-L, Nakashatri, H, Philippe, M, Chambon, P & Dolle, P (1994) Stage and tissue-specific expression of the alcohol dehydrogenase 1 (adh-1) gene during mouse development. Developmental Dynamics 199, 199–213.CrossRefGoogle ScholarPubMed
Wagner, M, Han, B & Jessell, TM (1992) Regional differences in retinoid release from embryonic neural tissue detected by an in vitro reporter assay. Development 116, 55–66.CrossRefGoogle ScholarPubMed
White, JA, Beckett-Jones, B, Guo, Y-D, Dilworth, FJ, Bonasoro, J, Jones, G & Petkovich, M (1997) cDNA cloning of human retinoic acid-metabolizing enzyme (hp450RAI) identifies a novel family of cytochromes P450 (CYP26). Journal of Biological Chemistry 272, 18538–18541.CrossRefGoogle ScholarPubMed
White, JA, Guo, Y-D, Baetz, K, Beckett-Jones, B, Bonasoro, J, Hsu, E, Dilworth, FJ, Jones, G & Petkovich, M (1996) Identification of the retinoic acid-inducible all-trans-retinoic acid 4-hydroxylase. Journal of Biological Chemistry 271, 29922–29927.CrossRefGoogle ScholarPubMed
White, JC, Shankar, VN, Highland, M, Epstein, ML, DeLuca, HF & Clagett-Dame, M (1998) 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. Proceedings of the National Academy of Sciences USA 95, 13459–13464.CrossRefGoogle ScholarPubMed
Wolbach, SB & Howe, PR (1925) Tissue changes following deprivation of fat soluble A vitamin. Journal of Experimental Medicine 42, 753–777.CrossRefGoogle ScholarPubMed
Zhao, D, McCaffery, P, Ivins, KJ, Neve, RL, Hogan, P, Chin, WW & Drager, UC (1996) Molecular identification of a major retinoic acid-synthesising enzyme, a retinaldehyde-specific dehydrogenase. European Journal of Biochemistry 240, 15–22.CrossRefGoogle Scholar