Limb regeneration: a new development?

Salamander limb regeneration is a classical model of tissue morphogenesis and patterning. Through recent advances in cell labeling and molecular analysis, a more precise, mechanistic understanding of this process has started to emerge. Long-standing questions include to what extent limb regeneration recapitulates the events observed in mammalian limb development and to what extent are adult- or salamander- specific aspects deployed. Historically, researchers studying limb development and limb regeneration have proposed different models of pattern formation. Here we discuss recent data on limb regeneration and limb development to argue that although patterning mechanisms are likely to be similar, cell plasticity and signaling from nerves play regeneration-specific roles.

[1]  S. Odelberg.  Cellular plasticity in vertebrate regeneration. , 2005, Anatomical record. Part B, New anatomist.

[2]  J. C. Belmonte,et al.  Zebrafish heart regeneration occurs by cardiomyocyte dedifferentiation and proliferation , 2010, Nature.

[3]  S. Bryant,et al.  Expression of Mmp‐9 and related matrix metalloproteinase genes during axolotl limb regeneration , 1999, Developmental dynamics : an official publication of the American Association of Anatomists.

[4]  Testing the clockface model of amphibian limb regeneration , 1978, Experientia.

[5]  D. SUMMERBELL,et al.  Positional Information in Chick Limb Morphogenesis , 1973, Nature.

[6]  D. Stocum.  Regulation after proximal or distal transposition of limb regeneration blastemas and determination of the proximal boundary of the regenerate. , 1975, Developmental biology.

[7]  D. Stocum,et al.  Epidermal‐mesodermal interaction during morphogenesis of the limb regeneration blastema in larval salamanders , 1972 .

[8]  Ruijin Huang,et al.  Amniote somite derivatives , 2007, Developmental dynamics : an official publication of the American Association of Anatomists.

[9]  Takahito Watanabe,et al.  Regulation of leg size and shape by the Dachsous/Fat signalling pathway during regeneration , 2009, Development.

[10]  R. Zeller,et al.  Gremlin-mediated BMP antagonism induces the epithelial-mesenchymal feedback signaling controlling metanephric kidney and limb organogenesis , 2004, Development.

[11]  M Maden,et al.  Intercalary regeneration in the amphibian limb and the rule of distal transformation. , 1980, Journal of embryology and experimental morphology.

[12]  M. Maden,et al.  The cellular contributions of blastema and stump to 180 ° supernumerary limbs in the axolotl , 1984 .

[13]  A. Satoh,et al.  Transgenic Xenopus with prx1 limb enhancer reveals crucial contribution of MEK/ERK and PI3K/AKT pathways in blastema formation during limb regeneration. , 2007, Developmental biology.

[14]  V. French,et al.  Distal regeneration and symmetry. , 1981, Science.

[15]  S. Bryant,et al.  Frequency of supernumerary limbs following blastemal rotations in the newt , 1980 .

[16]  G. Campbell.  Distalization of the Drosophila leg by graded EGF-receptor activity , 2002, Nature.

[17]  M. Singer.  NEUROTROPHIC CONTROL OF LIMB REGENERATION IN THE NEWT * , 1974, Annals of the New York Academy of Sciences.

[18]  A. Kuroiwa,et al.  Coordinated expression of Hoxa-11 and Hoxa-13 during limb muscle patterning. , 1998, Development.

[19]  C. Lien,et al.  fgf20 Is Essential for Initiating Zebrafish Fin Regeneration , 2005, Science.

[20]  S. Bryant,et al.  Distal transformation from double-half forearms in the axolotl, Ambystoma mexicanum. , 1980, Developmental biology.

[21]  András Simon,et al.  Salamander limb regeneration involves the activation of a multipotent skeletal muscle satellite cell population , 2006, The Journal of cell biology.

[22]  D. Gardiner,et al.  Cyclopamine induces digit loss in regenerating axolotl limbs. , 2002, The Journal of experimental zoology.

[23]  P. B. Gates,et al.  Functional convergence of signalling by GPI-anchored and anchorless forms of a salamander protein implicated in limb regeneration , 2011, Journal of Cell Science.

[24]  Denis Duboule,et al.  The role of Hox genes during vertebrate limb development. , 2007, Current opinion in genetics & development.

[25]  H. Meinhardt.  A bootstrap model for the proximodistal pattern formation in vertebrate limbs. , 1983, Journal of embryology and experimental morphology.

[26]  T. P. Steen.  Origin and differentiative capacities of cells in the blastema of the regenerating salamander limb. , 1970, American zoologist.

[27]  C. Tabin,et al.  Sonic hedgehog and Fgf-4 act through a signaling cascade and feedback loop to integrate growth and patterning of the developing limb bud , 1994, Cell.

[28]  P. Beachy,et al.  Manifestation of the limb prepattern: limb development in the absence of sonic hedgehog function. , 2001, Developmental biology.

[29]  Andrew P. McMahon,et al.  Signal relay by BMP antagonism controls the SHH/FGF4 feedback loop in vertebrate limb buds , 1999, Nature.

[30]  R. Zeller.  The temporal dynamics of vertebrate limb development, teratogenesis and evolution. , 2010, Current opinion in genetics & development.

[31]  H. Iba,et al.  Misexpression of Hoxa-13 induces cartilage homeotic transformation and changes cell adhesiveness in chick limb buds. , 1995, Genes & development.

[32]  J. Slack,et al.  Requirement for Wnt and FGF signaling in Xenopus tadpole tail regeneration. , 2008, Developmental biology.

[33]  D. A. Dunis,et al.  The role of grafted skin in the regeneration of x-irradiated axolotl limbs. , 1977, Developmental biology.

[34]  D. Melton,et al.  Self-organizational capacity of distally transplanted limb regeneration blastemas in larval salamanders. , 1977, The Journal of experimental zoology.

[35]  Donald Thomas Chalkley,et al.  A quantitative histological analysis of forelimb regeneration in triturus viridescens , 1954 .

[36]  S. Bryant,et al.  Regenerative ability of double-half and half upper arms in the newt, Notophthalmus viridescens. , 1978, The Journal of experimental zoology.

[37]  M. Maden,et al.  The structure of 180° supernumerary limbs and a hypothesis of their formation , 1982 .

[38]  Experiments on Anuran limb buds and their significance for principles of vertebrate limb development. , 1981, Journal of embryology and experimental morphology.

[39]  M. Capecchi,et al.  Absence of radius and ulna in mice lacking hoxa-11 andhoxd-11 , 1995, Nature.

[40]  Anoop Kumar,et al.  The Regenerative Plasticity of Isolated Urodele Myofibers and Its Dependence on Msx1 , 2004, PLoS biology.

[41]  H. Meinhardt,et al.  A boundary model for pattern formation in vertebrate limbs. , 1983, Journal of embryology and experimental morphology.

[42]  V. French,et al.  Pattern regulation in epimorphic fields. , 1976, Science.

[43]  D. Drachman.  Trophic functions of the neuron , 1974 .

[44]  N. Mercader,et al.  Proximodistal identity during vertebrate limb regeneration is regulated by Meis homeodomain proteins , 2005, Development.

[45]  H. Yamamoto,et al.  Expression of Msx genes in regenerating and developing limbs of axolotl. , 1998, The Journal of experimental zoology.

[46]  J. W. Saunders.  The proximo-distal sequence of origin of the parts of the chick wing and the role of the ectoderm. , 1948, The Journal of experimental zoology.

[47]  A. Jaźwińska,et al.  IGF signaling between blastema and wound epidermis is required for fin regeneration , 2010, Development.

[48]  J. I. Izpisúa Belmonte,et al.  Control of vertebrate limb outgrowth by the proximal factor Meis2 and distal antagonism of BMPs by Gremlin. , 1999, Molecular cell.

[49]  B. Goodwin,et al.  Experiments on developing limb buds of the axolotl Ambystoma mexicanum. , 1980, Journal of embryology and experimental morphology.

[50]  M. Marchionni,et al.  Cloning and neuronal expression of a type III newt neuregulin and rescue of denervated, nerve-dependent newt limb blastemas by rhGGF2. , 2000, Journal of neurobiology.

[51]  D. Stocum.  The urodele limb regeneration blastema: a self-organizing system. i. Differentiation in vitro. , 1968, Developmental biology.

[52]  E. Hay.  Electron microscopic observations of muscle dedifferentiation in regenerating amblystoma limbs , 1959 .

[53]  Julien Sage,et al.  Transient inactivation of Rb and ARF yields regenerative cells from postmitotic mammalian muscle. , 2010, Cell stem cell.

[54]  R. N. Turner,et al.  Supernumerary limbs in the axolotl , 1978, Nature.

[55]  Koji Tamura,et al.  Specification of cell fate along the proximal-distal axis in the developing chick limb bud , 2007, Development.

[56]  P. Tank.  The failure of double-half forelimbs to undergo distal transformation following amputation in the axolotl, Ambystoma mexicanum. , 1978, The Journal of experimental zoology.

[57]  P. Pietsch.  Differentiation in regeneration. I. The development of muscle and cartilage following deplantation of of regenerating limb blastemata of Amblystoma larvae. , 1961, Developmental biology.

[58]  P. B. Gates,et al.  The Meis homeoprotein regulates the axolotl Prod 1 promoter during limb regeneration , 2011, Gene.

[59]  S. Bryant,et al.  Nerve dependency of regeneration: the role of Distal-less and FGF signaling in amphibian limb regeneration. , 1996, Development.

[60]  Determination of axial polarity in the urodele limb regeneration blastema. , 1982, Journal of embryology and experimental morphology.

[61]  J. Couso,et al.  Leg Patterning Driven by Proximal-Distal Interactions and EGFR Signaling , 2002, Science.

[62]  C. Tabin,et al.  Analysis of Hox gene expression in the chick limb bud. , 1996, Development.

[63]  M. Maden.  Supernumerary Limbs in Amphibians , 1982 .

[64]  M. Maden.  The regeneration of positional information in the amphibian limb. , 1977, Journal of theoretical biology.

[65]  H. Sasaki,et al.  Correlation between Shh expression and DNA methylation status of the limb-specific Shh enhancer region during limb regeneration in amphibians. , 2007, Developmental biology.

[66]  D. Stocum,et al.  The origin of skeletal structures during intercalary regeneration of larval Ambystoma limbs. , 1980, Developmental biology.

[67]  E. Hay,et al.  Origin of the blastema in regenerating limbs of the newt Triturus viridescens. An autoradiographic study using tritiated thymidine to follow cell proliferation and migration. , 1961, Developmental biology.

[68]  M. Namenwirth.  The inheritance of cell differentiation during limb regeneration in the axolotl. , 1974, Developmental biology.

[69]  G. Martin,et al.  The roles of FGFs in the early development of vertebrate limbs. , 1998, Genes & development.

[70]  P. Tank.  Pattern formation following 180° rotation of regeneration blastemas in the axolotl, Ambystoma mexicanum , 1981 .

[71]  D. Summerbell.  Regulation of the deficiencies along the proximal distal axis of the chick wing-bud: a quantitative analysis. , 1977, Journal of embryology and experimental morphology.

[72]  R. Nusse,et al.  Wnt and FGF signals interact to coordinate growth with cell fate specification during limb development , 2008, Development.

[73]  H. Bohn.  Regeneration of proximal tissues from a more distal amputation level in the insect leg (Blaberus craniifer, Blattaria). , 1976, Developmental biology.

[74]  Elmer G. Butler,et al.  Regeneration of the urodele forelimb after reversal of its proximo‐distal axis , 1955 .

[75]  S. Bryant,et al.  Cellular contribution from dermis and cartilage to the regenerating limb blastema in axolotls. , 1986, Developmental biology.

[76]  E. Tanaka,et al.  Hedgehog signaling controls dorsoventral patterning, blastema cell proliferation and cartilage induction during axolotl tail regeneration , 2005, Development.

[77]  D. Stocum,et al.  Retinoic acid proximalizes level-specific properties responsible for intercalary regeneration in axolotl limbs. , 1988, Development.

[78]  J. C. Belmonte,et al.  Dedifferentiation, transdifferentiation and reprogramming: three routes to regeneration , 2011, Nature Reviews Molecular Cell Biology.

[79]  A. Kuroiwa,et al.  Retinoic acid changes the proximodistal developmental competence and affinity of distal cells in the developing chick limb bud. , 1997, Developmental biology.

[80]  H. Bohn.  Analyse der Regenerationsfähigkeit der Insektenextremität durch Amputations-und Transplantationsversuche an Larven der afrikanischen Schabe (Leucophaea maderae Fabr.) , 1965, Wilhelm Roux' Archiv für Entwicklungsmechanik der Organismen.

[81]  J. Brockes,et al.  The aneurogenic limb: a puzzle in cell interactions , 1987, Trends in Neurosciences.

[82]  B. Wallace,et al.  Participation of grafted nerves in amphibian limb regeneration. , 1973, Journal of embryology and experimental morphology.

[83]  S. Bryant,et al.  Regulation of HoxA expression in developing and regenerating axolotl limbs. , 1995, Development.

[84]  J. An,et al.  Expression patterns of Fgf‐8 during development and limb regeneration of the axolotl , 2001, Developmental dynamics : an official publication of the American Association of Anatomists.

[85]  G. Halder,et al.  Boundaries of Dachsous Cadherin activity modulate the Hippo signaling pathway to induce cell proliferation , 2008, Proceedings of the National Academy of Sciences.

[86]  H. Wallace,et al.  Duplicated axolotl regenerates. , 1979, Journal of embryology and experimental morphology.

[87]  S. Bryant,et al.  A stepwise model system for limb regeneration. , 2004, Developmental biology.

[88]  Hans-Georg Simon,et al.  Different regulation of T-box genes Tbx4 and Tbx5 during limb development and limb regeneration. , 2002, Developmental biology.

[89]  C. Tickle,et al.  FGF-4 replaces the apical ectodermal ridge and directs outgrowth and patterning of the limb , 1993, Cell.

[90]  V. French.  Leg regeneration in the cockroach, Blatella germanica. II. Regeneration from a non-congruent tibial graft/host junction. , 1976, Journal of embryology and experimental morphology.

[91]  M. Keating,et al.  Heart Regeneration in Zebrafish , 2002, Science.

[92]  Lewis Wolpert,et al.  Rethinking the proximodistal axis of the vertebrate limb in the molecular era. , 2007, Genes & development.

[93]  J. Fallon,et al.  Pattern regulation and the origin of extra parts following axial misalignments in the urodele limb bud. , 1980, Journal of embryology and experimental morphology.

[94]  A. Forge,et al.  A comparative study of gland cells implicated in the nerve dependence of salamander limb regeneration , 2010, Journal of anatomy.

[95]  Vladimir Vinarsky,et al.  Normal newt limb regeneration requires matrix metalloproteinase function. , 2005, Developmental biology.

[96]  D. Duboule.  Patterning in the vertebrate limb. , 1991, Current opinion in genetics & development.

[97]  C. Goodman,et al.  Dachsous encodes a member of the cadherin superfamily that controls imaginal disc morphogenesis in Drosophila. , 1995, Genes & development.

[98]  S. Bryant,et al.  Expression of Msx-2 during development, regeneration, and wound healing in axolotl limbs. , 1998, The Journal of experimental zoology.

[99]  S. Odelberg,et al.  A transitional extracellular matrix instructs cell behavior during muscle regeneration. , 2010, Developmental biology.

[100]  S. Bryant,et al.  Sonic hedgehog (shh) expression in developing and regenerating axolotl limbs. , 1999, The Journal of experimental zoology.

[101]  J. Brockes,et al.  Cell origin and identity in Limb regeneration and development , 1991, Glia.

[102]  P. Tank,et al.  The effect of healing time on the proximodistal organization of double-half forelimb regenerates in the axolotl, Ambystoma mexicanum. , 1978, Developmental biology.

[103]  R. Černý,et al.  Migratory patterns and developmental potential of trunk neural crest cells in the axolotl embryo , 2007, Developmental dynamics : an official publication of the American Association of Anatomists.

[104]  D. Stocum.  The urodele limb regeneration blastema: a self-organizing system. I. Morphogenesis and differentiation of autografted whole and fractional blastemas. , 1968, Developmental biology.

[105]  M. Maden,et al.  Vitamin A and pattern formation in the regenerating limb , 1982, Nature.

[106]  S. Bryant,et al.  Regeneration of symmetrical forelimbs in the axolotl, Ambystoma mexicanum. , 1980, Developmental biology.

[107]  Juan Carlos Izpisua Belmonte,et al.  Wnt/β-catenin signaling regulates vertebrate limb regeneration , 2006 .

[108]  E. Tanaka,et al.  Mechanisms of muscle dedifferentiation during regeneration. , 2002, Seminars in cell & developmental biology.

[109]  S. Bryant,et al.  The interaction between the blastema and stump in the establishment of the anterior--posterior and proximal--distal organization of the limb regenerate. , 1975, Developmental biology.

[110]  Mikiko Tanaka,et al.  Fibroblast growth factor‐induced gene expression and cartilage pattern formation in chick limb bud recombinants , 2001, Development, growth & differentiation.

[111]  S. Bryant,et al.  Analysis of the expression and function of Wnt‐5a and Wnt‐5b in developing and regenerating axolotl (Ambystoma mexicanum) limbs , 2008, Development, growth & differentiation.

[112]  D. Ornitz,et al.  FGF signaling regulates mesenchymal differentiation and skeletal patterning along the limb bud proximodistal axis , 2008, Development.

[113]  C. W. Bodemer.  The development of nerve‐induced supernumerary limbs in the adult newt, Triturus viridescens , 1958 .

[114]  C. Tabin,et al.  Differential expression of myogenic regulatory genes and Msx‐1 during dedifferentiation and redifferentiation of regenerating amphibian limbs , 1995, Developmental dynamics : an official publication of the American Association of Anatomists.

[115]  M. Maden.  The effect of vitamin A on the regenerating axolotl limb. , 1983, Journal of embryology and experimental morphology.

[116]  R. Zeller,et al.  Vertebrate limb bud development: moving towards integrative analysis of organogenesis , 2009, Nature Reviews Genetics.

[117]  R. Paro,et al.  Distinct Roles of Hand2 in Initiating Polarity and Posterior Shh Expression during the Onset of Mouse Limb Bud Development , 2010, PLoS genetics.

[118]  P. Tank.  The occurrence of supernumerary limbs following blastemal transplantation in the regenerating forelimb of the axolotl, Ambystoma mexicanum. , 1978, Developmental biology.

[119]  M. Singer.  On the Nature of the Neurotrophic Phenomenon in Urodele Limb Regeneration , 1978 .

[120]  J. Brockes,et al.  Activation of a single retinoic acid receptor isoform mediates proximodistal respecification , 1996, Current Biology.

[121]  M. Maden.  A test of the predictions of the boundary model regarding supernumerary limb structure. , 1983, Journal of embryology and experimental morphology.

[122]  Ginés Morata,et al.  Conserved regulation of proximodistal limb axis development by Meis1/Hth , 1999, Nature.

[123]  C. Antos,et al.  Vertebrates that regenerate as models for guiding stem cels. , 2010, Advances in experimental medicine and biology.

[124]  A. Satoh,et al.  Nerve-dependent and -independent events in blastema formation during Xenopus froglet limb regeneration. , 2005, Developmental biology.

[125]  R. Tassava,et al.  Apical epithelial cap morphology and fibronectin gene expression in regenerating axolotl limbs , 2000, Developmental dynamics : an official publication of the American Association of Anatomists.

[126]  P. B. Gates,et al.  Solution Structure and Phylogenetics of Prod1, a Member of the Three-Finger Protein Superfamily Implicated in Salamander Limb Regeneration , 2009, PloS one.

[127]  K. Yoshizato,et al.  Expression of Sonic hedgehog gene in regenerating newt limb blastemas recapitulates that in developing limb buds. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[128]  C. Tickle,et al.  ‘Regeneration’ of wing bud stumps of chick embryos and reactivation of Msx-1 and Shh expression in response to FGF-4 and ridge signals , 1996, Mechanisms of Development.

[129]  Dragana Rogulja,et al.  Regulation of Cell Proliferation by a Morphogen Gradient , 2005, Cell.

[130]  S. Bryant,et al.  Intercalary and supernumerary regeneration in regenerating the mature limbs of Notophthalmus viridescens. , 1977, The Journal of experimental zoology.

[131]  G. Schubiger,et al.  Three genes control the timing, the site and the size of blastema formation in Drosophila. , 2008, Developmental biology.

[132]  S. Bryant,et al.  Nerve-induced ectopic limb blastemas in the Axolotl are equivalent to amputation-induced blastemas. , 2007, Developmental biology.

[133]  H Wallace,et al.  Participation of cartilage grafts in amphibian limb regeneration. , 1974, Journal of embryology and experimental morphology.

[134]  P. B. Gates,et al.  The newt ortholog of CD59 is implicated in proximodistal identity during amphibian limb regeneration. , 2002, Developmental cell.

[135]  Anoop Kumar,et al.  Plasticity and reprogramming of differentiated cells in amphibian regeneration , 2002, Nature Reviews Molecular Cell Biology.

[136]  G. Halder,et al.  Hippo signaling: growth control and beyond , 2011, Development.

[137]  Elly M. Tanaka,et al.  Cells keep a memory of their tissue origin during axolotl limb regeneration , 2009, Nature.

[138]  S. Bryant.  Regenerative failure of double half limbs in Notophthalmus viridescens , 1976, Nature.

[139]  M. Weinstein,et al.  Expression of fibroblast growth factors 4, 8, and 10 in limbs, flanks, and blastemas of Ambystoma , 2002, Developmental dynamics : an official publication of the American Association of Anatomists.

[140]  S. Bryant,et al.  Neurotrophic regulation of epidermal dedifferentiation during wound healing and limb regeneration in the axolotl (Ambystoma mexicanum). , 2008, Developmental biology.

[141]  E. Tanaka,et al.  Proximodistal patterning during limb regeneration. , 2005, Developmental biology.

[142]  K. Poss,et al.  Advances in understanding tissue regenerative capacity and mechanisms in animals , 2010, Nature Reviews Genetics.

[143]  Anoop Kumar,et al.  Molecular Basis for the Nerve Dependence of Limb Regeneration in an Adult Vertebrate , 2007, Science.

[144]  J. Villano,et al.  four-jointed is required for intermediate growth in the proximal-distal axis in Drosophila. , 1995, Development.

[145]  B. Carlson.  The effects of rotation and positional change of stump tissues upon morphogenesis of the regenerating axolotl limb. , 1975, Developmental biology.

[146]  J. Slack.  Amphibian muscle regeneration--dedifferentiation or satellite cells? , 2006, Trends in cell biology.

[147]  M. Khokha,et al.  Gremlin is the BMP antagonist required for maintenance of Shh and Fgf signals during limb patterning , 2003, Nature Genetics.

[148]  Rolf Zeller,et al.  Vertebrate limb development: moving from classical morphogen gradients to an integrated 4-dimensional patterning system. , 2009, Cold Spring Harbor perspectives in biology.

[149]  P Chambon,et al.  Hoxa-13 and Hoxd-13 play a crucial role in the patterning of the limb autopod. , 1996, Development.

[150]  D. Stocum.  Regeneration of symmetrical hindlimbs in larval salamanders. , 1978, Science.

[151]  M. Maden.  Structure of supernumerary limbs , 1980, Nature.

[152]  R. N. Turner,et al.  Probability aspects of supernumerary production in the regenerating limbs of the axolotl, Ambystoma mexicanum. , 1981, Journal of embryology and experimental morphology.

[153]  C. Martínez-A,et al.  Opposing RA and FGF signals control proximodistal vertebrate limb development through regulation of Meis genes. , 2000, Development.

[154]  E. Ozawa,et al.  Myogenic cell migration from somites is induced by tissue contact with medial region of the presumptive limb mesoderm in chick embryos. , 1995, Development.

[155]  C. Tickle,et al.  The expression of Fat-1 cadherin during chick limb development. , 2007, The International journal of developmental biology.

[156]  G. Martin,et al.  Genetic evidence that FGFs have an instructive role in limb proximal–distal patterning , 2008, Nature.

[157]  M. Barna,et al.  Visualization of cartilage formation: insight into cellular properties of skeletal progenitors and chondrodysplasia syndromes. , 2007, Developmental cell.

[158]  Malcolm Maden,et al.  Axial characteristics of nerve induced supernumerary limbs in the axolotl , 1984, Wilhelm Roux's archives of developmental biology.

[159]  C. Tickle,et al.  A positive feedback loop coordinates growth and patterning in the vertebrate limb , 1994, Nature.

[160]  T. P. Steen.  Stability of chondrocyte differentiation and contribution of muscle to cartilage during limb regeneration in the axolotl (Siredon mexicanum). , 1968, The Journal of experimental zoology.

[161]  J. Brockes,et al.  Glial growth factor and nerve-dependent proliferation in the regeneration blastema of urodele amphibians , 1986, Cell.

[162]  S. Bryant,et al.  Supernumerary limgs in amphibians: experimental production in Notophthalmus viridescens and a new interpretation of their formation. , 1976, Developmental biology.