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RA Signaling in Limb Development and Regeneration in Different Species

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The Biochemistry of Retinoid Signaling III

Part of the book series: Subcellular Biochemistry ((SCBI,volume 95))

Abstract

This chapter brings together data on the role of retinoic acid (RA) in the embryonic development of fins in zebrafish , limbs in amphibians , chicks , and mice, and regeneration of the amphibian limb . The intention is to determine whether there is a common set of principles by which we can understand the mode of action of RA in both embryos and adults. What emerges from this synthesis is that there are indeed commonalities in the involvement of RA in processes that ventralize, posteriorize, and proximalize the developing and regenerating limb . Different axes of the limb have historically been studied independently; as for example, the embryonic development of the anteroposterior (AP) axis of the chick limb bud versus the regeneration of the limb bud proximodistal (PD) axis . But when we take a broader view, a unifying principle emerges that explains why RA administration to embryos and regenerating limbs results in the development of multiple limbs in both cases. As might be expected, different molecular pathways govern the development of different systems and model organisms, but despite these differences, the pathways involve similar RA signaling genes, such as tbx5, meis, shh, fgfs and hox genes. Studies of developing and regenerating systems have highlighted that RA acts by being synthesized in one embryonic location while acting in another one, exactly as embryonic morphogens do, although there is no evidence for the presence of an RA gradient within the limb . What also emerges is that there is a paucity of information on the involvement of RA in development of the dorsoventral (DV) axis . A molecular explanation as to how RA establishes and alters positional information in all three axes is the most important area of study for the future.

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Abbreviations

RA:

Retinoic acid

RAR:

Retinoic acid receptor

RARE:

Retinoic acid response element

RALDH:

Retinaldehyde dehydrogenase

ZPA:

Zone of polarizing activity

AP:

Anteroposterior

DV:

Dorsoventral

PD:

Proximodistal

DEAB:

Diethylaminobenzaldehyde

GFP:

Green fluorescent protein

AER:

Apical ectodermal ridge

EGFR:

Epidermal growth factor receptor

nAG:

Newt anterior gradient protein

HPLC:

High pressure liquid chromatography

References

  • Akimenko M-A, Ekker M (1995) Anterior duplication of the Sonic hedgehog expression pattern in the pectoral fin buds of zebrafish treated with retinoic acid. Dev Biol 170:243–247

    Article  CAS  PubMed  Google Scholar 

  • Alsop DH, Brown SB, van der Kraak GJ (2004) Dietary retinoic acid induces hindlimb and eye deformities in Xenopus laevis. Environ Sci Technol 38(23):6290–6299

    Article  CAS  PubMed  Google Scholar 

  • Begemann G, Schilling TF, Rauch G-J, Geisler R, Ingham PW (2001) The zebrafish neckless mutation reveals a requirement for raldh2 in mesodermal signal that pattern the hindbrain. Development 128:3081–3094

    CAS  PubMed  Google Scholar 

  • Begemann G, Marx M, Mebus K, Meyer A, Bastmeyer M (2004) Beyond the neckless phenotype: influence of reduced retinoic acid signaling on motor neuron development in the zebrafish hindbrain. Dev Biol 271:119–129

    Article  CAS  PubMed  Google Scholar 

  • Bénazet J-D, Bischofberger M, Tiecke E, Gonçalves A, Martin JF, Zuniga A, Naef F, Zeller R (2009) A self-regulatory system of interlinked signaling feedback loops controls mouse limb patterning. Science 323:1050–1053

    Article  PubMed  CAS  Google Scholar 

  • Berggren K, McCaffery P, Drager U, Forehand CJ (1999) Differential distribution of retinoic acid synthesis in the chicken embryo as determined by immunolocalization of the retinoic acid synthetic enzyme ALDH-2. Dev Biol 210:288–304

    Article  CAS  PubMed  Google Scholar 

  • Blassberg RA, Garza-Garcia A, Janmohamed A, Gates PB, Brockes JP (2010) Functional convergence of signaling by GPI-anchored and anchorless forms of a salamander protein implicated in limb regeneration. J Cell Sci 124:47–56

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Blentic A, Gale E, Maden M (2003) Retinoic acid signaling centres in the avian embryo identified by sites of expression of synthesizing and catabolizing enzymes. Dev Dynam 227:114–127

    Article  CAS  Google Scholar 

  • Brockes JP (1992) Introduction of a retinoid reporter gene into the urodele limb blastema. PNAS USA 89:11386–11390

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chen Y, Pollet N, Niehrs C, Peiler T (2001) Increased XRALDH2 activity has a posteriorizing effect on the ventral nervous systems of Xenopus embryos. Mech Dev 101:91–103

    Article  CAS  PubMed  Google Scholar 

  • Cohn M, Izpisua-Belmonte JC, Abud H, Heath JK, Tickle C (1995) Fibroblast growth factors induce additional limb development from the flank of chick embryos. Cell 80:739–746

    Article  CAS  PubMed  Google Scholar 

  • Cooper KL, Hu JK-H, Berge DT, Fernandez-Teran M, Ros MA, Tabin CJ (2011) Initiation of proximal-distal patterning in the vertebrate limb by signals and growth. Science 332:1083–1085

    Google Scholar 

  • Crawford K, Stocum DL (1988) Retinoic acid co-ordinately proximalizes regenerate pattern and blastema differential affinity in axolotl limbs. Development 102:687–698

    CAS  PubMed  Google Scholar 

  • Crick F (1970) Diffusion in embryogenesis. Nature 225:420–421

    Article  CAS  PubMed  Google Scholar 

  • Cuervo R, Chimal-Monroy J (1886) Chemical activation of RARb induces post-embryonically bilateral limb duplication during Xenopus limb regeneration. Sci Rep 3. https://doi.org/10.1038/srep01886

  • Cunningham TJ, Chatzi C, Sandell LL, Trainor PA, Duester G (2011) Rdh10 mutants deficient in limb field retinoic acid signaling exhibit normal limb patterning but display interdigital webbing. Dev Dyn 240:1142–1150

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cunningham TJ, Zhao X, Sandell LL, Evans SM, Trainor PA, Duester G (2013) Antagonism between retinoic acid and fibroblast growth signaling during limb development. Ce Rep 2:1503–1511

    Article  CAS  Google Scholar 

  • Degitz SJ, Holcombe GW, Kosian PA, Tietge JE, Durhan EJ, Ankley GT (2003) Comparing the effects of stage and duration of retinoic Acid exposure on amphibian limb development: chronic exposure results in mortality, not limb malformations. Toxicol Sci 74:139–146

    Article  CAS  PubMed  Google Scholar 

  • Del Rincon SV, Scadding SR (2002) Retinoid antagonists inhibit normal patterning during limb regeneration in the axolotl, Ambystoma mexicanum. J exp Zool. Part A. 292:435–444

    Article  Google Scholar 

  • Dobbs-McAuliffe B, Zhao Q, Linney E (2004) Feedback mechanisms regulate retinoic acid production and degradation in the zebrafish embryo Mech Dev. 121:339–350

    CAS  PubMed  Google Scholar 

  • Echeverri K, Tanaka EM (2005) Proximodistal patterning during limb regeneration. Dev Biol 279:391–401

    Article  CAS  PubMed  Google Scholar 

  • Elinson RP, Walton Z, Nath K. Raldh (2008) expression in embryos of the direct developing frog Eleutherodactylus coqui and the conserved retinoic acid requirement for forelimb initiation. J exp Zool (Mol. Dev. Biol) 310B:588–595

    Google Scholar 

  • Emoto Y, Wada H, Okamoto H, Kudo A, Imai Y (2005) Retinoic acid-metabolizing enzyme Cyp26a1 is essential for determining territories of hindbrain and spinal cord in zebrafish. Dev Biol 278:415–427

    Article  CAS  PubMed  Google Scholar 

  • Ephrussi A, St Johnston D (2004) Seeing is believing: the bicoid gradient matures. Cell 116:143–152

    Article  CAS  PubMed  Google Scholar 

  • French V, Bryant PJ, Bryant SV (1976) Pattern regulation in epimorphic fields. Science 193:969–981

    Article  CAS  PubMed  Google Scholar 

  • Gibert Y, Gajewski A, Mayer A, Begemann G (2006) Induction and prepatterning of the zebrafish pectoral fin bud requires axial retinoic acid signaling. Development 133:2649–2659

    Article  CAS  PubMed  Google Scholar 

  • Grandel H, Lun K, Rauch GJ, Rhinn M, Piotrowski T, Houart C, Sordino P, Küchler AM, Schulte-Merker S, Geisler R, Holder N, Wilson SW, Brand M (2002) Retinoic acid signalling in the zebrafish embryo is necessary during pre-segmentation stages to pattern the anterior-posterior axis of the CNS and to induce a pectoral fin bud. Development 129:2851–2865

    CAS  PubMed  Google Scholar 

  • Helms J, Thaller C, Eichele G (1994) Relationship between retinoic acid and sonic hedgehog, two polarizing signals in the chick wing bud. Development 120:3267–3274

    CAS  PubMed  Google Scholar 

  • Helms J, Kim CH, Thaller C, Eichele G (1996) Retinoic acid signaling is required during early limb development. Development 122:1385–1394

    CAS  PubMed  Google Scholar 

  • Horton C, Maden M (1995) Endogenous distribution of retinoids during normal development and teratogenesis in the mouse embryo. Dev Dyn 202:312–323

    Article  CAS  PubMed  Google Scholar 

  • Izpisúa-Belmonte J-C, Tickle C, Dollé P, Wolpert L, Duboule D (1991) Expression of homeobox Hox-4 genes and the specification of position in chick wing development. Nature 350:585–589

    Article  PubMed  Google Scholar 

  • Ju B-G, Kim W-S (1994) Pattern duplication by retinoic acid treatment in the regenerating limbs of Korean salamander larvae, Hynobius leechii, correlates well with the extent of dedifferentiation. Dev Dynam 199:253–267

    Article  CAS  Google Scholar 

  • Keegan BR, Feldman JL, Begemann G, Ingham PW, Yelon D (2005) Retinoic acid signaling restricts the cardiac progenitor pool. Science 307:247–249

    Article  CAS  PubMed  Google Scholar 

  • Kim W-S, Stocum DL (1990) Retinoic aic modifies positional memory in the anteroposterior axis of regenerating axolotl limbs. Dev Biol 114:170–179

    Article  Google Scholar 

  • Kumar A, Gates PB, Brockes JP (2007) Positional identity of adult stem cells in salamander limb regeneration. C.R. Biologies 330:485–490

    Google Scholar 

  • Kumar A, Godwin JW, Gates PB, Garza-Garcia AA, Brockes JP (2007b) Molecular basis for the nerve dependence of limb regeneration in an adult vertrbrate. Science 303:540–543

    Google Scholar 

  • Larsen HL, Janners MY (1987) Teratogenic effects of retinoic acid and dimethylsulfoxide on embryonic chick wing and somite. Teratology 36:313–320

    Article  CAS  PubMed  Google Scholar 

  • Lee GS, Kochhar DM, Collins MD (2004) Retinoid-induced limb malformations. Curr Pharm Des 10:2657–2699

    Article  CAS  PubMed  Google Scholar 

  • Lheureux E, Thoms SD, Carey F (1986) The effects of two retinoids on limb regeneration in Pleurodeles waltl and Triturus vulgaris. J Embryol Exp Morph 92:165–182

    CAS  PubMed  Google Scholar 

  • Liao X, Collins MD (2008) All-trans retinoic acid-induced ectopic limb and caudal structures: murine strain sensitivities and pathogenesis. Dev Dynam 237:1553–1564

    Article  CAS  Google Scholar 

  • Linville A, Radtke K, Waxman JS, Yelon D, Schilling TF (2009) Combinatorial roles for zebrafish retinoic acid receptors in the hindbrain, limbs and pharyngeal arches. Dev Biol 325:60–70

    Article  CAS  PubMed  Google Scholar 

  • Lu H-C, Eichele G, Thaller C (1997a) Ligand-bound RXR can mediate retinoid signal transduction during embryogenesis. Development 124:195–203

    CAS  PubMed  Google Scholar 

  • Lu H-C, Revelli J-P, Goering L, Thaller C, Eichele G (1997b) Retinoid signaling is required for the establishment of a ZPA and for the expression of Hoxb-8, a mediator of ZPA formation. Development 124:1643–1651

    CAS  PubMed  Google Scholar 

  • Ludolph DC, Cameron JA, Stocum DL (1990) The effect of retinoic acid on positional memory in the dorsoventral axis of regenerating axolotl limbs. Dev Biol 1990(140):41–52

    Article  Google Scholar 

  • Lynch J, McEwan J, Beck CW (2011) Analysis of the expression of retinoic acid metabolizing genes during Xenopus laevis organogenesis. Gene Exp Patt 11:112–117

    Article  CAS  Google Scholar 

  • MacLean G, Abu-Abed S, Dolle P, Tahayato A, Chambon P, Petkovich M (2001) Cloning of a novel retinoic acid- metabolizing cytochrome P450, Cyp26B1, and comparative expression analysis with Cyp26A1 during early murine development. Mech Dev 107:195–201

    Article  CAS  PubMed  Google Scholar 

  • Maden M (1978) Supernumerary limbs in the axolotl. Nature 273:232–235

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Maden M (1983a) The effect of vitamin A on the regenerating axolotl limb. J Embryol exp Morph 77:273–295

    CAS  PubMed  Google Scholar 

  • Maden M (1983b) The effect of vitamin A on limb regeneration in Rana temporaria. Dev Biol 98:409–416

    Article  CAS  PubMed  Google Scholar 

  • Maden M (1993) The homeotic transformation of tails into limbs in Rana temporaria by retinoids. Dev Biol 159:379–391

    Article  CAS  PubMed  Google Scholar 

  • Maden M (1998) Retinoids as endogenous components of the regenerating limb and tail. Wound Rep Regen. 6:358–365

    Article  CAS  Google Scholar 

  • Maden M, Sonneveld E, Van Der Saag PT, Gale E (1998) The distribution of retinoic acid in the chick embryo: implications for developmental mechanisms. Development 125:4133–4144

    CAS  PubMed  Google Scholar 

  • Mandal A, Rydeen A, Anderson J, Sorrell MR, Zygmunt T, Torres-Vázquez J, Waxman JS (2013) Transgenic retinoic acid sensor lines in zebrafish indicate regions of available embryonic retinoic acid. Dev Dyn 242:989–1000

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • McEwan J, Lynch J, Beck CW (2011) Expression of key retinoic acid modulating genes suggests active regulation during development and regeneration of the amphibian limb. Dev Dyn 240:1259–1270

    Article  CAS  PubMed  Google Scholar 

  • Mercarder N, Leonardo E, Peidra ME, Martinez-A C, Ros MA, Torres M (2000) Opposing RA and FGF signals control proximodistal vertebrate limb development through regulation of Meis genes. Development 127:3961–3970

    Google Scholar 

  • Mercarder N, Fischer S, Neumann CJ (2006) Prdm1 acts downstream of a sequential RA, Wnt and Fgf signaling cascade during zebrafish forelimb induction. Development 133:2805–2815

    Article  CAS  Google Scholar 

  • Mic FA, Sirbu IO, Duester G (2004) 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. J Biol Chem 279:26698–26706

    Article  CAS  PubMed  Google Scholar 

  • Mohanty-Heijmadi 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

    Article  Google Scholar 

  • Monaghan JR, Maden M (2012) Visualization of retinoic acid signaling in transgenic axolotls during limb development and regeneration. Dev Biol 368:63–75

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Monaghan JR, Athippozy A, Seifert AW, Putta S, Stromberg A, Maden M, Gardiner DM, Voss SR (2012) Gene expression patterns specific to the regenerating limb of the Mexican axolotl. Biol Open 1:937–948

    Article  PubMed  PubMed Central  Google Scholar 

  • Morais da Silva S, Gates PB, Brockes JP (2002) The Newt Ortholog of CD59 Is Implicated in Proximodistal Identity during Amphibian Limb Regeneration. Dev Cell 3:547–555

    Google Scholar 

  • Morgan TH (1901) Regeneration. Macmillan New York, 1901

    Google Scholar 

  • Nardi JB, Stocum DL (1983) Surface properties of regenerating limb cells: evidence for gradation along the proximodistal axis. Differentiation 25:27–31

    Article  Google Scholar 

  • Neumann CJ, Grandel H, Gaffield W, Schulte-Merker S, Nusslein-Volhard C (1999) Transient establishment of anteroposterior polarity in the zebrafish pectoral fin bud in the absence of sonic hedgehog activity. Development 126:4817–4826

    CAS  PubMed  Google Scholar 

  • Nguyen M, Singhal P, Piet J, Shefelbine SJ, Maden M, Voss AR, Monaghan JR (2017) Retinoic acid receptor regulation of epimorphic and homeostatic regeneration in the axolotl. Development 144:601–611

    Article  CAS  PubMed  Google Scholar 

  • Niazi IA, Saxena S (1978) Abnormal hindlimb regeneration in tadpoles of the toad, Bufo andersonii, exposed to excess vitamin A. Folia Biol (Krakow) 26:3–8

    CAS  Google Scholar 

  • Niazi IA, Pescitelli MJ, Stocum DL (1985) Stage dependent effects of retinoic acid on regenerating limbs. Wilhelm Roux Arch Dev Biol 194:355–363

    Article  CAS  Google Scholar 

  • Niederreither K, Subbarayan V, Dolle P, Chambon P (1999) Embryonic retinoic acid synthesis is essential for early mouse post-embryonic development. Nat Genet 21:444–448

    Article  CAS  PubMed  Google Scholar 

  • Niederreither K, Ward SJ, Dolle P, Chambon P (1996) Morphological and molecular characterization of retinoic acid-induced limb duplications in mice. Dev Biol 176:185–198

    Article  CAS  PubMed  Google Scholar 

  • Niswander L, Jeffrey S, Martin GR, Tickle C (1994) A positive feedback loop coordinates growth and patterning in the vertebrate limb. Nature 371:609–612

    Article  CAS  PubMed  Google Scholar 

  • Nohno T, Noji S, Koyama E, Ohyama K, Myokai F, Kuroiwa A, Saito T, Taniguchi S (1991) Involvement of Chox-4 chicken homeobox genes in determination of anteroposterior axial polarity during limb development. Cell 64:1197–1205

    Article  CAS  PubMed  Google Scholar 

  • Noji S, Nohno T, Koyama E, Muto K, Ohyama K, Yoshinobu A, Tamura K, Ohsugi K, Ide H, Taniguchi S, Saito T (1991) Retinoic acid induces polarizing activity but is unlikely to be a morphogen in the chick limb bud. Nature 350:83–86

    Article  CAS  PubMed  Google Scholar 

  • Oulad-Abdelghani M, Chazaud C, Bouillet P, Sapin V, Chambon P, Dolle P (1997) Meis2, a novel mouse Pbx-related homeobox gene induced by retinoic acid during differentiation of P19 embryonal carcinoma cells. Dev Dynam 210:173–183

    Article  CAS  Google Scholar 

  • Pecorino LT, Lo DC, Brockes JP (1994) Isoform-specific induction of a retinoid-responsive antigen after biolistic transfection of chimeric retinoic acid/thyroid hormone receptors into a regenerating limb. Development 120:325–333

    CAS  PubMed  Google Scholar 

  • Pecorino LT, Entwistle A, Brockes JP (1996) Activation of a single retinoic acid receptor isoform mediates proximodistal respecification. Curr Biol 6:563–569

    Article  CAS  PubMed  Google Scholar 

  • Perez-Edwards A, Hardison NL, Linney E (2001) Retinoic acid-mediated gene expression in transgenic reporter zebrafish. Dev Biol 229:89–101

    Article  CAS  Google Scholar 

  • Pickering J, Wali N, Towers M (2017) Transcriptional changes in chick wing bud polarization induced by retinoic acid. Dev Dyn 246:682–690

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pittlik S, Begemann G (2012) New sources of retinoic acid synthesis revealed by live imaging of an Aldh1a2-GFP reporter fusion protein throughout zebrafish development. Dev Dyn 241:1205–1216

    Article  CAS  PubMed  Google Scholar 

  • Probst S, Kraemer C, Demougin P, Sheth R, Martin GR, Shiratori H, Hamada H, Iber D, Zeller R, Zuniga A (2011) SHH propagates distal limb bud development by enhancing CYP26B1-mediated retinoic acid clearance via AER-FGF signaling. Development 138:1913–1923

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Reijntjes S, Gale E, Maden M (2003) Expression of the retinoic acid catabolizing enzyme CYP26B1 in the chick embryo and its regulation by retinoic acid. Gene Exp Patt 3:621–627

    Article  CAS  Google Scholar 

  • Reijntjes S, Zile MH, Maden M (2010) The expression of Stra6 and Rdh10 in the avian embryo and their contribution to the generation of retinoid signatures. Int J Dev Biol 54:1267–1275

    Article  CAS  PubMed  Google Scholar 

  • Rhinn M, Schubaur B, Niederreither K, Dolle P (2011) Involvement of retinol dehydrogenase 10 in embryonic patterning and rescue of its loss of function by maternal retinaldehyde treatment. PNAS USA 108:16687–16692

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Riddle RD, Johnson RL, Laufer E, Tabin C (1993) Sonic hedgehog mediates the polarizing activity of the ZPA. Cell 75:1401–1416

    Article  CAS  PubMed  Google Scholar 

  • Rosello-Diez A, Ros MA, Torres M (2011) Diffusable signals, not autonomous mechanisms, determine the main proximodistal limb subdivisions. Science 332:1086–1088

    Article  CAS  PubMed  Google Scholar 

  • Rutledge JC, Shourbaji AG, Hughes LA, Polifka JE, Cruz YP, Bishop JB, Generoso WM (1994) Limb and lower-body duplications induced by retinoic acid in mice. PNAS USA 91:5436–5440

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sandell LL, Sanderson BW, Moiseyev G, Johnson T, Mushegian, A, Young, Rey J-P, Ma J, Staeling-Hampton K, Trainor PA (2007) RDH10 is essential for synthesis of embryonic retinoic acid and is required for limb, craniofacial, and organ development. Genes Dev 21:1113–1124

    Google Scholar 

  • Satre MA, Kochhar DM (1989) Elevations in the endogenous levels of the putative morphogen retinoic acid in the embryonic mouse limb buds associated with limb dysmorphogenesis. Dev Biol 133:529–536

    Article  CAS  PubMed  Google Scholar 

  • Saunders JW, Gasseling MT (1968) Ectodermal-mesenchymal interactions in the origins of limb asymmetry. In Epithelial-Mesenchymal Interactions eds Fleischmajer R, Billingham RE. pp 78–97. Baltimore, Williams & Watkins

    Google Scholar 

  • Scadding SR (1999) Citral, an inhibitor of retinoic acid synthesis, modifies pattern formation during limb regeneration in the axolotl Ambystoma mexicanum. Canad J Zool 77:1835–1837

    Article  CAS  Google Scholar 

  • Scadding SR, Maden M (1986a) Comparison of the effects of vitamin A on limb development and regeneration in Xenopus laevis tadpoles. J Embryol exp Morph. 91:35–53

    CAS  PubMed  Google Scholar 

  • Scadding SR, Maden M (1986b) Comparison of the effects of vitamin A on limb development and regeneration in the axolotl. Ambystoma mexicanum. J Embryol exp Morph. 91:19–34

    CAS  PubMed  Google Scholar 

  • Scadding SR, Maden M (1994) Retinoic acid gradients in limb regeneration. Dev Biol 162:608–617

    Article  CAS  PubMed  Google Scholar 

  • Schilthius JG, Gann AA, Brockes JP (1993) Chimeric retinoic acid/thyroid hormone receptors implicate RAR-alpha 1 as mediating growth inhibition by retinoic acid. EMBO J 12:3459–3466

    Article  Google Scholar 

  • Scott WJ, Walter R, Tzimas G, Sass JO, Nau H, Collins MD (1994) Endogenous status of retinoids and their cytosolic binding proteins in limb buds of chick vs mouse embryos. Dev Biol 165:397–409

    Article  CAS  PubMed  Google Scholar 

  • Shaikh N, Gates PB, Brockes JP (2011) The Meis homeoprotein regulates the axolotl Prod 1 promoter during limb regeneration. Gene 484:69–74

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shenefelt RA (1972) Morphogenesis of malformations in hamsters casued by retinoic acid: REaltion to dose and stage of tretement. Teratology 5:103–118

    Article  CAS  PubMed  Google Scholar 

  • Shimozono S, Iimura T, Kitaguchi T, Higashijima S, Miyawaki A (2013) Visualization of an endogenous retinoic acid gradient across embryonic development. Nature 496:363–366

    Article  CAS  PubMed  Google Scholar 

  • Slack JMW (1987) We have a morphogen! Nature 327:553–554

    Article  CAS  PubMed  Google Scholar 

  • Sonneveld E, van den Brink CE, van der Leede BM, Maden M, van der Saag PT (1999) Embryonal carcinoma cell lines stably transfected with mRARβ2-lacZ: sensitive system for measuring levels of active retinoids. Exp Cell Res 250:284–297

    Article  CAS  PubMed  Google Scholar 

  • Stocum DL, Thoms SD (1984) Retinoic-acid-induced pattern completion in regenerating double anterior limbs of urodeles. J Exp Zool 232:207–215

    Article  CAS  PubMed  Google Scholar 

  • Stratford T, Horton C, Maden M (1996) Retinoic acid is required for the initiation of outgrowth in the chick limb bud. Curr Biol 6:1124–1133

    Article  CAS  PubMed  Google Scholar 

  • Stratford T, Kostakopoulou K, Maden M (1997) Hoxb-8 has a role in establishing early anterior-posterior polarity in chick forelimb but not in hindlimb. Development 124:4225–4234

    CAS  PubMed  Google Scholar 

  • Stratford T, Logan C, Zile M, Maden M (1999) Abnormal anteroposterior and dorsoventral patterning of the limb bud in the absence of retinoids. Mech Dev 81:115–125

    Article  CAS  PubMed  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 Morph 78:269–289

    CAS  PubMed  Google Scholar 

  • Swindell EC, Thaller C, Sockanathan S, Petkovich M, Jessell TM, Eichele G (1999) Complementary domains of retinoic acid production and degradation in the early chick embryo. Dev Biol 216:282–296

    Article  CAS  PubMed  Google Scholar 

  • Tamura K, Aoki Y, Ide H (1993) Induction of polarizing activity by retinoic acid occurs independently of duplicate formation in developing chick limb buds. Dev Biol 158:341–349

    Article  CAS  PubMed  Google Scholar 

  • Tamura K, Yokouchi Y, Kuroiwa A, Ide H (1997) Retinoic acid changes the proximodistal developmental competence and affinity of distal cells in the developing chick limb bud. Dev Biol 188:224–234

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Thaller C, Eichele G (1988) Characterization of retinoid metabolism in the developing chick limb bud. Development 103:473–483

    CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Thoms SD, Stocum DL (1984) Retinoic acid-induced pattern duplication in regenerating urodele limbs. Dev Biol 103:319–328

    Article  CAS  PubMed  Google Scholar 

  • Tickle C (1981) The number of polarizing region cells required to specify additional digits in the developing chick wing. Nature 289:295–298

    Article  CAS  PubMed  Google Scholar 

  • Tickle C, Summerbell D, Wolpert L (1975) Positional signaling and specification of digits in the chick wing bud. J Embryo exp Morph Nature 254:199–202

    CAS  Google Scholar 

  • Tickle C, Alberts B, Wolpert L, Lee J (1982) Local application of retinoic acid to the limb bond mimics the action of the polarizing region. Nature 296:564–566

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Uzkudun M, Marcon L, Sharpe J (2015) Data-driven modelling of a gene regulatory network for cell fate decisions in the growing limb bud. Mol Sys Biol. 11:815

    Article  CAS  Google Scholar 

  • Vandersea MW, Fleming P, McCarthy RA, Smith DG (1998) Fin duplications and deletions induced by disruptions of retinoic acid signaling. Dev Gene Evol. 208:61–68

    Article  CAS  Google Scholar 

  • Viviano CM, Horton CE, Maden M, Brockes JP (1995) Synthesis and release of 9-cis retinoic acid by the urodele wound epidermis. Development 1221:3753–3762

    Google Scholar 

  • Voss SR, Murrugara D, Jensen TB, Monaghan JR (2018) Transcriptional correlates of proximal-distal identity and regeneration timing in axolotl limbs. Comp Biochem Physiol Part C 208:53–63

    Google Scholar 

  • Wakahara T, Kusu N, Yamauchi H, Kimura I, Konishi M, Miyake A, Itoh N (2007) fibin, a novel secreted lateral plate mesoderm signal, is essential for pectoral fin bud initiation in zebrafish. Dev Biol 303:527–535

    Article  CAS  PubMed  Google Scholar 

  • Wanek N, Gardiner DM, Muneoka K, Bryant SV (1991) Conversion by retinoic acid of anterior cells into ZPA cells in the chick wing bud. Nature 350:81–83

    Article  CAS  PubMed  Google Scholar 

  • Waxman JS, Yelon D (2011) Zebrafish retinoic acid receptors function as context-dependent transcriptional activators. Dev Biol 352:128–140

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • White RJ, Nie Q, Lander AD, Schilling TF (2007) Complex regulation of cyp26a1 creates a robust retinoic acid gradient in the zebrafish embryo. PLoS Biol 5:e304

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Wigmore P (1990) Serially duplicated regenerates from the anterior half of the axolotl limb after retinoic acid treatment. Roux’s Arch Dev Biol 198:252–256

    Article  Google Scholar 

  • Wilde SM, Wedden SE, Tickle C (1987) Retinoids reprogramme pre-bud mesenchyme to give changes in limb pattern. Development 100:723–733

    CAS  PubMed  Google Scholar 

  • Wolpert L (1969) Positional information and the spatial pattern of cellular differentiation. J Theor Biol 25:1–47

    Article  CAS  PubMed  Google Scholar 

  • Yakushiji-Kaminatsui N, Kondo T, Hironaka K, Sharif J, Endo TA, Nakayama M, Masui O, Koseki Y, Kondo K, Ohara O, Vidal M, Morishita Y, Koseki H (2018) Variant PRC1 competes with retinoic acid-related signals to repress Meis2 in the mouse distal forelimb bud. Development 145:dev166348

    Google Scholar 

  • Yashiro K, Zhao X, Uehara M, Yamashita K, Nishijima M, Nishino J, Saijoh Y, Sakai Y, Hamada H (2004) Regulation of retinoic acid distribution is required for proximodistal patterning and outgrowth of the developing mouse limb. Dev Cell 6:411–422

    Article  CAS  PubMed  Google Scholar 

  • Zeller R, López-Ríos J, Zuniga A (2009) Vertebrate limb bud development: moving towards integrative analysis of organogenesis Nat Rev Gen 10:845–858

    CAS  Google Scholar 

  • Zhao X, Sirbu IO, Mic FA, Molotkova N, Molotkov A, Kumar S, Duester G (2009) Retinoic acid promotes limb induction through effects on body axis extension but is unnecessary for limb patterning. Current Biol 19:1050–1057

    Article  CAS  Google Scholar 

  • Zhao D, McCaffery P, Ivins KJ, Neve RL, Hogan P, Chin WW, Dräger UC (1996) Molecular identification of a major retinoic-acid-synthesizing enzyme, a retinaldehyde-specific dehydrogenase. Eur J Biochem 240:15–22

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

I wish to thank Nicole Serrano for her excellent drawing skills displayed in Fig. 4.3.

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  1. Department of Biology, Department of Biology, UF Genetics Institute, University of Florida, Gainesville, USA

    Malcolm Maden

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  1. Malcolm Maden
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Correspondence to Malcolm Maden .

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  1. Maine Medical Center Research Institute, Scarborough, ME, USA

    Mary Ann Asson-Batres

  2. Département of Functional Génomics and Cancer, Institut de Genetique et de Biologie Moleculaire et Cellulaire (IGBMC), Illkirch, France

    Cecile Rochette-Egly

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Maden, M. (2020). RA Signaling in Limb Development and Regeneration in Different Species. In: Asson-Batres, M., Rochette-Egly, C. (eds) The Biochemistry of Retinoid Signaling III. Subcellular Biochemistry, vol 95. Springer, Cham. https://doi.org/10.1007/978-3-030-42282-0_4

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