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Retinoic acid in development and regeneration

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Abstract

Retinoids are low molecular weight, lipophilic derivatives of vitamin A which have profound effects upon the development of various embryonic systems. Here I review the effects on developing and regenerating limbs, regenerating amphibian tails and the developing central nervous system (CNS). In the regenerating amphibian limb, retinoids can proximalize, posteriorize and ventralize the axes of the blastema. In the chick limb bud retinoids can only posteriorize the tissue. In the regenerating amphibian tail retinoids can homeotically transform tail tissue into hindlimb tissue. In the developing and regenerating limb retinoic acid has been detected endogenously, confirming that this molecule plays a role in the generation of pattern and we have shown that limbs cannot develop in the absence of retinoic acid. In the developing CNS retinoic acid specifically affects the hindbrain where it causes a transformation of anterior rhombomeres into more posterior ones. Again, endogenous retinoic acid has been detected in the CNS and in the absence of retinoids the posterior hindbrain has been found to be affected. The effects of retinoids on the CNS are most likely to be mediated via theHox genes acting in the mesoderm after gastrulation. It has also been proposed that the establishment of the head-to-tail axis in the mesoderm is established by retinoic acid. These data show that retinoids play an important role in both the development and regeneration of various systems in the embryo and post-embryonically

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References

  • Alexandre D, Clarke J D W, Oxtoby E, Yan Y-L, Jowett T and Holder N 1996 Ectopic expression ofHoxa-1 in the zebrafish alters the fate of mandibular arch neural crest and phenocopies a retinoic acid-induced phenotype:Development 122 735–746

    PubMed  CAS  Google Scholar 

  • Bryant S V and Gardiner D M 1992 Retinoic acid, local cell-cell interactions and pattern formation in vertebrate limbs;Dev. Biol. 152 1–25

    Article  PubMed  CAS  Google Scholar 

  • Brockes J P 1992 Introduction of a retinoid reporter gene into the urodele limb blastema;Proc. Natl. Acad. Sci. USA 89 11386–11390

    Article  PubMed  CAS  Google Scholar 

  • Chen Y, Huang L, Russo A F and Solursh M 1992 Retinoic acid is enriched in Hensen’s node and is developmentally regulated in the early chicken embryo;Proc. Natl. Acad. Sci. USA 89 10056–10059

    Article  PubMed  CAS  Google Scholar 

  • Chen Y and Solursh M 1992 Comparison of Hensen’s node and retinoic acid in secondary axis induction in the early chick embryo;Dev. Dynamics 195 142–151

    CAS  Google Scholar 

  • Child C M 1915Individuality in organisms (Univ. Chicago Press)

  • Cho K W Y and De Robertis E M 1990 Differential activation ofX enopus homeobox genes by mesoderminducing growth factors and retinoic acid;Genes Dee. 4 1910–1916

    Article  CAS  Google Scholar 

  • Cohlan S Q 1953 Excessive intake of vitamin A as a cause of congenital abnormalities in the rat;Science 117 535

    Article  PubMed  CAS  Google Scholar 

  • Crick F H C 1970 Diffusion in embryogenesis;Nature (London) 225 420–422

    Article  CAS  Google Scholar 

  • Driesch H 1892 Entwicklungsmechanische Studien. I Der Werth der beid en ersten Furchungszellen in der Echinodermenentwicklung. Experimentelle Erzeugen von Theil-und Doppelbildung;Z. Wiss. Zool. 53160–178

    Google Scholar 

  • Dersch H and Zile M H 1993 Induction of normal cardiovascular development in the vitamin A-deprived quail embryo by natural retinoids;Dev. Biol. 160 424–433

    Article  PubMed  CAS  Google Scholar 

  • Durston A J, Timmermans J P M, Hage W Hendriks H F J, de Vries N J, Heideveld M and Nieuwkoop P D 1989 Retinoic acid causes an anteroposterior transformation in the developing central nervous system;Nature (London) 340 140–144

    Article  CAS  Google Scholar 

  • 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. CellBiol. 101 1913–1920

    Article  CAS  Google Scholar 

  • Gurdon J B, Harger P, Mitchell A and Lemaire P 1994 Activin signalling and response to a morphogen gradient;Nature (London) 371 487–492

    Article  CAS  Google Scholar 

  • Hill J, Clarke J D W, Vargesson N, Jowett T and Holder N 1995 Exogenous retinoic acid causes specific alterations in the midbrain and hindbrain of the zebrafish embryo including positional respecification of the Mauthner neuron;Mech. Dev. 50 3–16

    Article  PubMed  CAS  Google Scholar 

  • Hogan B L M, Thaller C and Eichele G 1992 Evidence that Hensen’s node is a site of retinoic acid synthesis;Nature (London) 359 237–241

    Article  CAS  Google Scholar 

  • Holder N and Hill J 1991 Retinoic acid modifies development of the midbrain-hindbrain border and affects cranial ganglion formation in zebrafish embryos;Development 113 1159–1170

    PubMed  CAS  Google Scholar 

  • Horton C and Maden M 1995 Endogenous distribution of retinoids during normal development and teratogenesis in the mouse embryo;Dev. Dynam. 202 312–323

    CAS  Google Scholar 

  • Keeble S and Maden M 1989 The relationship among retinoid structure, affinity for retinoic acid-binding protein and ability to respecify pattern in the regenerating axolotl limb;Dev. Biol. 132 26–34

    Article  PubMed  CAS  Google Scholar 

  • Kim W-S and StocumD L 1986 Retinoic acid modifies positional memory in the anteroposterior axis of regenerating axolotl limbs;Dev. Biol. 114 170–179

    Article  PubMed  CAS  Google Scholar 

  • Lammer E J, Chen D T, Hoar R M, Agnish A D, Benke P J, Braun J T, Curry C J, Fernhoff P M, Grix A W, Lott I T, Richard J M and Sun S C 1985 Retinoic acid embryopathy;New Eng. J. Med. 313 837–841

    Article  PubMed  CAS  Google Scholar 

  • Lheureux E. Thorns S D and Carey F 1986 The effects of two retinoids in limb regeneration inPleurodeles waitl andTriturus vulgaris;J. Embryol. Exp. Morphol. 92 165–182

    PubMed  CAS  Google Scholar 

  • Ludolph D C, Cameron J A and Stocum D L 1990 The effects of retinoic acid on positional memory in the dorsoventral axis of regenerating axolotl limbs;Dev. Biol. 140 41–52

    Article  PubMed  CAS  Google Scholar 

  • Maden M 1982 Vitamin A and pattern formation in the regenerating limb;Nature (London) 295 672–675

    Article  CAS  Google Scholar 

  • Maden M 1983a The effect of vitamin A on the regenerating axolotl limb;J. Embryol. Exp. Morphol. 77 273–295

    PubMed  CAS  Google Scholar 

  • Maden M 1983b The effect of vitamin A on limb regeneration inRana temporaria;Dev. Biol. 98 409–416

    Article  PubMed  CAS  Google Scholar 

  • Maden M 1984 Does vitamin A act on pattern formation via the epidermis or mesenchyme?;J. Exp. Zool. 230 387–392

    Article  CAS  Google Scholar 

  • Maden M 1993 The homeotic transformation of tails into limbs by retinoids inRana temporaria;Dev. Biol 159 379–391

    Article  PubMed  CAS  Google Scholar 

  • Maden M, Gale E, Horton C and Smith J C 1992 Retinoid-binding proteins in the developing vertebrate nervous system; inRetinoids in normal development and teratogenesis (ed.) G Morriss-Kay (Oxford: Oxford University Press) pp 119–134

    Google Scholar 

  • 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;Differentiation 47 49–55

    Article  PubMed  CAS  Google Scholar 

  • Mahapatra P K and Mohanty-Hejmadi P 1994 Vitamin A-mediated homeotic transformation of tail to limbs, limb suppression and abnormal tail regeneration in the Indian jumping frogPolypedates maculatus;Dev. Growth Differ. 36 307–317

    Article  CAS  Google Scholar 

  • Marshall H, Nonchev S, Sham M H, Muchamore I, Lumsden A and K Rumlaufr 1992 Retinoic acid alters hindbrainHox code and induced transformation of rhombomeres 2/3 into a 4/5 identity;Nature (London) 360 737–741

    Article  CAS  Google Scholar 

  • McCaffery P, Lee M, Wagner M A, Sladek N E and Drager U C 1993 Changing patterns of the retinoic acid system in the developing retina;Dev. Biol. 158 390–399

    Article  CAS  Google Scholar 

  • Mohanty-Hejmadi P, Dutta S K and Mahapatra P 1991 Limbs generated at the site of amputation in marbled balloon frog after vitamin A treatment;Nature (London) 355 352–353

    Article  Google Scholar 

  • Morgan T H 1906 “Polarity” considered as a phenomenon of gradation of materials;J. Exp. Zoo!. 2 495

    Article  Google Scholar 

  • Morriss G M 1972 Morphogenesis of the malformations induced in rat embryos by maternal hypervitaminosis A;J. Anat. 113 241–250

    PubMed  CAS  Google Scholar 

  • Niazi I A and Saxena S 1978 Abnormal hind limb regeneration in tadpoles of the toad,Bufo andersoni, exposed to excess vitamin A;Folio Biol. (Krakow) 26 3–8

    CAS  Google Scholar 

  • Niazi I A and Saxena S 1979 Relationship between inhibiting influence of vitamin A and developmental stage of regenerating tail in toad tadpoles(Bufo andersonii);Indian J. Exp. Biol. 17 866–868

    PubMed  CAS  Google Scholar 

  • Niazi I A, Pescitelli M J and Stocum D L 1985 Stage dependent effects of retinoic acid on regenerating urodele limbs;Roux’s Arch. Dev. Biol. 194 355–363

    Article  CAS  Google Scholar 

  • Noji S, Nohno T, Koyama E, Muto K, Ohyama K, Aoki Y, Tamura K, Ohsugi K, Ide H, Taniguchi S and Sato T 1991 Retinoic acid induces polarizing activity but is unlikely to be a morphogen in the chick limb bud;Nature (London) 350 83–86

    Article  CAS  Google Scholar 

  • Papalopulu N, Clarke J D W, Bradley L, Wilkinson D, Krumlauf R and Holder N 1991 Retinoic acid causes abnormal development and segmental patterning of the anterior hindbrain inXenopus embryos;Development 113 1145–1158

    PubMed  CAS  Google Scholar 

  • Riddle R D, Johnson R L, Laufer E and Tabin C 1993 Sonic hedgehog mediates the polarizing activity of the ZPA;Cell 75 1401–1416

    Article  PubMed  CAS  Google Scholar 

  • Saunders J W and Gasseling M T 1968 Ectodermal-mesodermal interactions in the origin of limb symmetry; inEpithelial-mesenchymal interactions (eds) R Fleischmajer and R E Billingham (Baltimore: Williams and Wilkins Co) pp 79–97

    Google Scholar 

  • Scadding S R 1987 Vitamin A inhibits amphibian tail regenerates;Can. J. Zool. 65 457–459

    CAS  Google Scholar 

  • Scadding S R and Maden M 1986 Comparison of the effects of the vitamin A on limb development and regenerationin Xenopus laevis tadpoles;J. Embryol.Exp. Morphol. 91 35–53

    PubMed  CAS  Google Scholar 

  • Scadding S R and Maden M 1994 Retinoic acid gradients in limb regeneration;Dev. Biol. 162 608–617

    Article  PubMed  CAS  Google Scholar 

  • Scott W J, Walter R, Tzimas G, Sass J O, Nau H and Collins M D 1994 Endogenous status of retinoids and their cytosolic binding proteins in limb buds of chick vs mouse embryos;Dev. Biol. 165 397–409

    Article  PubMed  CAS  Google Scholar 

  • Sharpe C R 1991 Retinoic acid can mimic endogenous signals involved in transformation of theXenopus nervous system;Neuron 7 239–247

    Article  PubMed  CAS  Google Scholar 

  • Sive H L, Draper B W, Harland R M and Wientraub H 1990 Identification of a retinoic acid-sensitive period during primary axis formation inXenopus laevis;Genes Dev. 4 932–942

    Article  PubMed  CAS  Google Scholar 

  • Smith J C 1979 Evidence for a positional memory in the development of the chick wing bud;J Embryol. Exp. Morphol. 52 105–113

    PubMed  CAS  Google Scholar 

  • Stocum D L and Thoms S D 1984 Retinoic acid induced pattern completion in regenerating double anterior limbs of urodeles;J. Exp. Zool. 232 207–215

    Article  PubMed  CAS  Google Scholar 

  • Summerbell D 1983 The effect of local application of retinoic acid to the anterior margin of the developing chick limb;J. Embryol. Exp. Morphol. 78 269–298

    PubMed  CAS  Google Scholar 

  • Summerbell D and Harvey F 1983 Vitamin A and the control of pattern in developing limbs; inLimb development and regeneration. Part A (eds) J F Fallon and A I Caplan (New York: Alan R, Liss Inc) pp 109–118

    Google Scholar 

  • Summerbell D and Honig L S 1982 The control of pattern across the antero-posterior axis of the chick limb bud by a unique signalling region; Am.Zool. 22 105–116

    Google Scholar 

  • Thaller C and Eichele G 1987 Identification and spatial distribution of retinoids in the developing chick limb bud;Nature (London) 327 625–628

    Article  CAS  Google Scholar 

  • Thaller C and Eichele G 1990 Isolation of 3,4-didehydroretinoic acid, a novel morphogenetic signal in the chick wing bud;Nature (London) 345 815–819

    Article  CAS  Google Scholar 

  • Thompson J N, Howell J M, Pitt G A J and McLaughlin C I 1969 The biological activity of retinoic acid in the domestic fowl and the effects of vitamin A deficiency on the chick embryo;Br. J. Nutr. 23 471–490

    Article  PubMed  CAS  Google Scholar 

  • Thorns S D and Slocum D L 1984 Retinoic acid-induced pattern duplication in regenerating urodele limbs;Dev.Biol. 103 319–328

    Article  Google Scholar 

  • Tickle C, Alberts B, Wolpert L and Lee J 1982 Local application of retinoic acid to the limb bud mimics the action of the polarizing region;Nature (London) 296 564–565

    Article  CAS  Google Scholar 

  • Tickle C, Crawley A and Farrer J 1989 Retinoic acid application to chick wing buds leads to a dosedependent reorganization of the apical ectodermal ridge that is mediated by the mesenchyme;Development 106 691–705

    PubMed  CAS  Google Scholar 

  • Tickle C, Lee J and Eichele G 1985 A quantitative analysis of the effects of all-trans-retinoic acid on the pattern of chick wing development;Dev. Biol. 109 82–95

    Article  PubMed  CAS  Google Scholar 

  • Tickle C, Summerbell D and Wolpert L 1975 Positional signalling and specification of digits in chick limb mo rphogenesis;Nature (London) 254 199–202

    Article  CAS  Google Scholar 

  • Wagner M, Han B and Jessell T M 1992 Regional differences in retinoid release from embryonic neural tissue detected by anin vitro reporter assay;Development 116 55–66

    PubMed  CAS  Google Scholar 

  • Wagner M, Thaller C, Jessell T and Eichele G 1990 Polarizing activity and retinoid synthesis in the floor plate of the neural tube;Nature (London) 345 819–822

    Article  CAS  Google Scholar 

  • Wanek J, Gardiner D M, Muneoka K and Bryant S V 1991 Conversion by retinoic acid of anterior cells into ZPA cells in the chick wing bud;Nature (London) 350 81–83

    Article  CAS  Google Scholar 

  • Wigmore P 1990 Serially duplicated regenerates from the anterior half of the axolotl limb after retinoic acid treatment;Roux’sArch. Dev. Biol. 198 252–256

    Article  Google Scholar 

  • Wolpert L 1969 Positional information and the spatial pattern of cellular differentiation;J. Theor. Biol. 15 1–47

    Article  Google Scholar 

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Maden, M. Retinoic acid in development and regeneration. J Biosci 21, 299–312 (1996). https://doi.org/10.1007/BF02703090

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