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Embryology and Classification of Congenital Upper Limb Anomalies

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Congenital Anomalies of the Upper Extremity

Abstract

Understanding the etiologies underlying congenital limb anomalies is an important step in developing corrective or preventative therapies. To accomplish this task, knowledge of how the limb develops is crucial. The position of limb outgrowth is under precise molecular control. In addition, the subsequent growth and differentiation of the limb are tightly regulated by a complex network of signaling molecules secreted by specialized zones in the limb, known as signaling centers. Any disruption in the regulation of these molecules can cause dysmorphogenesis or dysplasias that result in congenital limb anomalies. This chapter will review recent insights from developmental biology, clinical genetics, and hand surgery that define our current understanding of how limb anomalies occur.

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References

  1. O’Rahilly R, Muller F. Developmental stages in human embryos. Washington, DC: Carnegie Institution of Washington; 1987.

    Google Scholar 

  2. Tickle C. Embryology. In: AKS Gupta (Ed.), The growing hand: diagnosis and management of the upper extremity in children. Sheker LR. London: CV Mosby; 2000;25–32.

    Google Scholar 

  3. Cohn MJ, Tickle C. Developmental basis of limblessness and axial patterning in snakes. Nature. 1999;399(6735):474–9.

    CAS  PubMed  Google Scholar 

  4. Burke AC, Nelson CE, Morgan BA, Tabin C. Hox genes and the evolution of vertebrate axial morphology. Development. 1995;121(2):333–46.

    CAS  PubMed  Google Scholar 

  5. Searls RL, Janners MY. The initiation of limb bud outgrowth in the embryonic chick. Dev Biol. 1971;24(2):198–213.

    CAS  PubMed  Google Scholar 

  6. Kawakami Y, Capdevila J, Buscher D, Itoh T, Rodriguez Esteban C, Izpisua Belmonte JC. WNT signals control FGF-dependent limb initiation and AER induction in the chick embryo. Cell. 2001;104(6):891–900.

    CAS  PubMed  Google Scholar 

  7. Ohuchi H, Nakagawa T, Yamamoto A, Araga A, Ohata T, Ishimaru Y, Yoshioka H, Kuwana T, Nohno T, Yamasaki M, et al. The mesenchymal factor, FGF10, initiates and maintains the outgrowth of the chick limb bud through interaction with FGF8, an apical ectodermal factor. Development. 1997;124(11):2235–44.

    CAS  PubMed  Google Scholar 

  8. Minguillon C, Del Buono J, Logan MP. Tbx5 and Tbx4 are not sufficient to determine limb-specific morphologies but have common roles in initiating limb outgrowth. Dev Cell. 2005;8(1):75–84.

    CAS  PubMed  Google Scholar 

  9. Minguillon C, Nishimoto S, Wood S, Vendrell E, Gibson-Brown JJ, Logan MP. Hox genes regulate the onset of Tbx5 expression in the forelimb. Development. 2012;139(17):3180–8.

    CAS  PubMed Central  PubMed  Google Scholar 

  10. Pizette S, Abate-Shen C, Niswander L. BMP controls proximodistal outgrowth, via induction of the apical ectodermal ridge, and dorsoventral patterning in the vertebrate limb. Development. 2001;128(22):4463–74.

    CAS  PubMed  Google Scholar 

  11. Soshnikova N, Zechner D, Huelsken J, Mishina Y, Behringer RR, Taketo MM, Crenshaw III EB, Birchmeier W. Genetic interaction between Wnt/beta-catenin and BMP receptor signaling during formation of the AER and the dorsal-ventral axis in the limb. Genes Dev. 2003;17(16):1963–8.

    CAS  PubMed Central  PubMed  Google Scholar 

  12. Barrow JR, Thomas KR, Boussadia-Zahui O, Moore R, Kemler R, Capecchi MR, McMahon AP. Ectodermal Wnt3/beta-catenin signaling is required for the establishment and maintenance of the apical ectodermal ridge. Genes Dev. 2003;17(3):394–409.

    CAS  PubMed Central  PubMed  Google Scholar 

  13. Abu-Abed S, Dolle P, Metzger D, Beckett B, Chambon P, Petkovich M. The retinoic acid-metabolizing enzyme, CYP26A1, is essential for normal hindbrain patterning, vertebral identity, and development of posterior structures. Genes Dev. 2001;15(2): 226–40.

    CAS  PubMed Central  PubMed  Google Scholar 

  14. Hogan BL, Thaller C, Eichele G. Evidence that Hensen’s node is a site of retinoic acid synthesis. Nature. 1992;359(6392): 237–41.

    CAS  PubMed  Google Scholar 

  15. Niederreither K, McCaffery P, Drager UC, Chambon P, Dolle P. Restricted expression and retinoic acid-induced downregulation of the retinaldehyde dehydrogenase type 2 (RALDH-2) gene during mouse development. Mech Dev. 1997;62(1):67–78.

    CAS  PubMed  Google Scholar 

  16. Cunningham TJ, Zhao X, Sandell LL, Evans SM, Trainor PA, Duester G. Antagonism between retinoic acid and fibroblast growth factor signaling during limb development. Cell Rep. 2013;3(5):1503–11.

    CAS  PubMed Central  PubMed  Google Scholar 

  17. Zhao X, Sirbu IO, Mic FA, Molotkova N, Molotkov A, Kumar S, Duester G. Retinoic acid promotes limb induction through effects on body axis extension but is unnecessary for limb patterning. Curr Biol. 2009;19(12):1050–7.

    CAS  PubMed Central  PubMed  Google Scholar 

  18. Kessel M, Gruss P. Homeotic transformations of murine vertebrae and concomitant alteration of Hox codes induced by retinoic acid. Cell. 1991;67(1):89–104.

    CAS  PubMed  Google Scholar 

  19. Deschamps J. Ancestral and recently recruited global control of the Hox genes in development. Curr Opin Genet Dev. 2007;17(5):422–7.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  21. Fallon JF, Kelley RO. Ultrastruct analysis of the apical ectodermal ridge during vertebrate limb morphogenesis. II. Gap junctions as distinctive ridge structures common to birds and mammals. J Embryol Exp Morphol. 1977;41:223–32.

    CAS  PubMed  Google Scholar 

  22. Summerbell D, Lewis JH. Time, place and positional value in the chick limb-bud. J Embryol Exp Morphol. 1975;33(3):621–43.

    CAS  PubMed  Google Scholar 

  23. Chiang C, Litingtung Y, Harris MP, Simandl BK, Li Y, Beachy PA, Fallon JF. Manifestation of the limb prepattern: limb development in the absence of sonic hedgehog function. Dev Biol. 2001;236(2):421–35.

    CAS  PubMed  Google Scholar 

  24. Ros MA, Dahn RD, Fernandez-Teran M, Rashka K, Caruccio NC, Hasso SM, Bitgood JJ, Lancman JJ, Fallon JF. The chick oligozeugodactyly (ozd) mutant lacks sonic hedgehog function in the limb. Development. 2003;130(3):527–37.

    CAS  PubMed  Google Scholar 

  25. MacCabe JA, Errick J, Saunders Jr JW. Ectodermal control of the dorsoventral axis in the leg bud of the chick embryo. Dev Biol. 1974;39(1):69–82.

    CAS  PubMed  Google Scholar 

  26. Lewandoski M, Sun X, Martin GR. Fgf8 signalling from the AER is essential for normal limb development. Nat Genet. 2000;26(4):460–3.

    CAS  PubMed  Google Scholar 

  27. Fernandez-Teran M, Ros MA. The Apical Ectodermal Ridge: morphological aspects and signaling pathways. Int J Dev Biol. 2008;52(7):857–71.

    PubMed  Google Scholar 

  28. Niswander L, Tickle C, Vogel A, Booth I, Martin GR. FGF-4 replaces the apical ectodermal ridge and directs outgrowth and patterning of the limb. Cell. 1993;75(3):579–87.

    CAS  PubMed  Google Scholar 

  29. Fallon JF, Lopez A, Ros MA, Savage MP, Olwin BB, Simandl BK. FGF-2: apical ectodermal ridge growth signal for chick limb development. Science. 1994;264(5155):104–7.

    CAS  PubMed  Google Scholar 

  30. Mariani FV, Ahn CP, Martin GR. Genetic evidence that FGFs have an instructive role in limb proximal-distal patterning. Nature. 2008;453(7193):401–5.

    CAS  PubMed Central  PubMed  Google Scholar 

  31. Sun X, Lewandoski M, Meyers EN, Liu YH, Maxson Jr RE, Martin GR. Conditional inactivation of Fgf4 reveals complexity of signalling during limb bud development. Nat Genet. 2000;25(1):83–6.

    CAS  PubMed  Google Scholar 

  32. Sun X, Mariani FV, Martin GR. Functions of FGF signalling from the apical ectodermal ridge in limb development. Nature. 2002;418(6897):501–8.

    CAS  PubMed  Google Scholar 

  33. Boulet AM, Moon AM, Arenkiel BR, Capecchi MR. The roles of Fgf4 and Fgf8 in limb bud initiation and outgrowth. Dev Biol. 2004;273(2):361–72.

    CAS  PubMed  Google Scholar 

  34. Summerbell D, Lewis JH, Wolpert L. Positional information in chick limb morphogenesis. Nature. 1973;244(5417):492–6.

    CAS  PubMed  Google Scholar 

  35. Summerbell D, Wolpert L. Precision of development in chick limb morphogenesis. Nature. 1973;244(5413):228–30.

    CAS  PubMed  Google Scholar 

  36. Dudley AT, Ros MA, Tabin CJ. A re-examination of proximodistal patterning during vertebrate limb development. Nature. 2002;418(6897):539–44.

    CAS  PubMed  Google Scholar 

  37. Tabin C, Wolpert L. Rethinking the proximodistal axis of the vertebrate limb in the molecular era. Genes Dev. 2007;21(12):1433–42.

    CAS  PubMed  Google Scholar 

  38. Rosello-Diez A, Ros MA, Torres M. Diffusible signals, not autonomous mechanisms, determine the main proximodistal limb subdivision. Science. 2011;332(6033):1086–8.

    CAS  PubMed  Google Scholar 

  39. Rosello-Diez A, Torres M. Regulative patterning in limb bud transplants is induced by distalizing activity of apical ectodermal ridge signals on host limb cells. Dev Dyn. 2011;240(5):1203–11.

    PubMed  Google Scholar 

  40. Yashiro K, Zhao X, Uehara M, Yamashita K, Nishijima M, Nishino J, Saijoh Y, Sakai Y, Hamada H. Regulation of retinoic acid distribution is required for proximodistal patterning and outgrowth of the developing mouse limb. Dev Cell. 2004;6(3): 411–22.

    CAS  PubMed  Google Scholar 

  41. Knezevic V, De Santo R, Schughart K, Huffstadt U, Chiang C, Mahon KA, Mackem S. Hoxd-12 differentially affects preaxial and postaxial chondrogenic branches in the limb and regulates Sonic hedgehog in a positive feedback loop. Development. 1997;124(22):4523–36.

    CAS  PubMed  Google Scholar 

  42. Saunders JW, Gasseling MT. Ectodermal-mesenchymal interactions in the origin of limb symmetry. In: Fleischmajer R, Billingham RE, editors. Epithelial-mesenchymal interactions. Baltimore: William and Wilkins; 1968. p. 78–97.

    Google Scholar 

  43. Tickle C, Summerbell D, Wolpert L. Positional signalling and specification of digits in chick limb morphogenesis. Nature. 1975;254(5497):199–202.

    CAS  PubMed  Google Scholar 

  44. Tickle C. Limb regeneration. Am Sci. 1981;69(6):639–46.

    CAS  PubMed  Google Scholar 

  45. Tickle C, Lee J, Eichele G. A quantitative analysis of the effect of all-trans-retinoic acid on the pattern of chick wing development. Dev Biol. 1985;109(1):82–95.

    CAS  PubMed  Google Scholar 

  46. Tickle C, Crawley A, Farrar J. Retinoic acid application to chick wing buds leads to a dose-dependent reorganization of the apical ectodermal ridge that is mediated by the mesenchyme. Development. 1989;106(4):691–705.

    CAS  PubMed  Google Scholar 

  47. Tickle C. Retinoic acid and chick limb bud development. Dev Suppl. 1991;1:113–21.

    CAS  PubMed  Google Scholar 

  48. Wanek N, Gardiner DM, Muneoka K, Bryant SV. Conversion by retinoic acid of anterior cells into ZPA cells in the chick wing bud. Nature. 1991;350(6313):81–3.

    CAS  PubMed  Google Scholar 

  49. Riddle RD, Johnson RL, Laufer E, Tabin C. Sonic hedgehog mediates the polarizing activity of the ZPA. Cell. 1993;75(7): 1401–16.

    CAS  PubMed  Google Scholar 

  50. Kraus P, Fraidenraich D, Loomis CA. Some distal limb structures develop in mice lacking Sonic hedgehog signaling. Mech Dev. 2001;100(1):45–58.

    CAS  PubMed  Google Scholar 

  51. Xu B, Wellik DM. Axial Hox9 activity establishes the posterior field in the developing forelimb. Proc Natl Acad Sci U S A. 2011;108(12):4888–91.

    CAS  PubMed Central  PubMed  Google Scholar 

  52. Zeller R, Lopez-Rios J, Zuniga A. Vertebrate limb bud development: moving towards integrative analysis of organogenesis. Nat Rev Genet. 2009;10(12):845–58.

    CAS  PubMed  Google Scholar 

  53. Charitè J, McFadden DG, Olson EN. The bHLH transcription factor dHAND controls Sonic hedgehog expression and establishment of the zone of polarizing activity during limb development. Development. 2000;127(11):2461–70.

    PubMed  Google Scholar 

  54. Capellini TD, Di GG, Salsi V, Brendolan A, Ferretti E, Srivastava D, Zappavigna V, Selleri L. Pbx1/Pbx2 requirement for distal limb patterning is mediated by the hierarchical control of Hox gene spatial distribution and Shh expression. Development. 2006;133(11):2263–73.

    CAS  PubMed  Google Scholar 

  55. Zakany J, Kmita M, Duboule D. A dual role for Hox genes in limb anterior-posterior asymmetry. Science. 2004;304(5677):1669–72.

    CAS  PubMed  Google Scholar 

  56. Schimmang T, Lemaistre M, Vortkamp A, Ruther U. Expression of the zinc finger gene Gli3 is affected in the morphogenetic mouse mutant extra-toes (Xt). Development. 1992;116(3): 799–804.

    CAS  PubMed  Google Scholar 

  57. Hui CC, Joyner AL. A mouse model of greig cephalopolysyndactyly syndrome: the extra-toesJ mutation contains an intragenic deletion of the Gli3 gene. Nat Genet. 1993;3(3):241–6.

    CAS  PubMed  Google Scholar 

  58. Litingtung Y, Dahn RD, Li Y, Fallon JF, Chiang C. Shh and Gli3 are dispensable for limb skeleton formation but regulate digit number and identity. Nature. 2002;418(6901):979–83.

    CAS  PubMed  Google Scholar 

  59. te Welscher P, Zuniga A, Kuijper S, Drenth T, Goedemans HJ, Meijlink F, Zeller R. Progression of vertebrate limb development through SHH-mediated counteraction of GLI3. Science. 2002;298(5594):827–30.

    Google Scholar 

  60. McGlinn E, van Bueren KL, Fiorenza S, Mo R, Poh AM, Forrest A, Soares MB, Bonaldo Mde F, Grimmond S, Hui CC, et al. Pax9 and Jagged1 act downstream of Gli3 in vertebrate limb development. Mech Dev. 2005;122(11):1218–33.

    CAS  PubMed  Google Scholar 

  61. Parr BA, McMahon AP. Dorsalizing signal Wnt-7a required for normal polarity of D-V and A-P axes of mouse limb. Nature. 1995;374(6520):350–3.

    CAS  PubMed  Google Scholar 

  62. Loomis CA, Harris E, Michaud J, Wurst W, Hanks M, Joyner AL. The mouse Engrailed-1 gene and ventral limb patterning. Nature. 1996;382(6589):360–3.

    CAS  PubMed  Google Scholar 

  63. Logan C, Hornbruch A, Campbell I, Lumsden A. The role of Engrailed in establishing the dorsoventral axis of the chick limb. Development. 1997;124(12):2317–24.

    CAS  PubMed  Google Scholar 

  64. Cygan JA, Johnson RL, McMahon AP. Novel regulatory interactions revealed by studies of murine limb pattern in Wnt-7a and En-1 mutants. Development. 1997;124(24):5021–32.

    CAS  PubMed  Google Scholar 

  65. Loomis CA, Kimmel RA, Tong CX, Michaud J, Joyner AL. Analysis of the genetic pathway leading to formation of ectopic apical ectodermal ridges in mouse Engrailed-1 mutant limbs. Development. 1998;125(6):1137–48.

    CAS  PubMed  Google Scholar 

  66. Riddle RD, Ensini M, Nelson C, Tsuchida T, Jessell TM, Tabin C. Induction of the LIM homeobox gene Lmx1 by WNT7a establishes dorsoventral pattern in the vertebrate limb. Cell. 1995;83(4): 631–40.

    CAS  PubMed  Google Scholar 

  67. Vogel A, Rodriguez C, Warnken W, Izpisua Belmonte JC. Dorsal cell fate specified by chick Lmx1 during vertebrate limb development. Nature. 1995;378(6558):716–20.

    CAS  PubMed  Google Scholar 

  68. Zuniga A, Haramis AP, McMahon AP, Zeller R. Signal relay by BMP antagonism controls the SHH/FGF4 feedback loop in vertebrate limb buds. Nature. 1999;401(6753):598–602.

    CAS  PubMed  Google Scholar 

  69. Michos O, Panman L, Vintersten K, Beier K, Zeller R, Zuniga A. Gremlin-mediated BMP antagonism induces the epithelial-mesenchymal feedback signaling controlling metanephric kidney and limb organogenesis. Development. 2004;131(14):3401–10.

    CAS  PubMed  Google Scholar 

  70. Bandyopadhyay A, Tsuji K, Cox K, Harfe BD, Rosen V, Tabin CJ. Genetic analysis of the roles of BMP2, BMP4, and BMP7 in limb patterning and skeletogenesis. PLoS Genet. 2006;2(12):e216.

    PubMed Central  PubMed  Google Scholar 

  71. Benazet JD, Bischofberger M, Tiecke E, Goncalves A, Martin JF, Zuniga A, Naef F, Zeller R. A self-regulatory system of interlinked signaling feedback loops controls mouse limb patterning. Science. 2009;323(5917):1050–3.

    CAS  PubMed  Google Scholar 

  72. Verheyden JM, Sun X. An Fgf/Gremlin inhibitory feedback loop triggers termination of limb bud outgrowth. Nature. 2008; 454(7204):638–41.

    CAS  PubMed Central  PubMed  Google Scholar 

  73. Yang Y, Niswander L. Interaction between the signaling molecules WNT7a and SHH during vertebrate limb development: dorsal signals regulate anteroposterior patterning. Cell. 1995;80(6):939–47.

    CAS  PubMed  Google Scholar 

  74. Fernandez-Teran M, Ros MA, Mariani FV. Evidence that the limb bud ectoderm is required for survival of the underlying mesoderm. Dev Biol. 2013;381(2):11.

    Google Scholar 

  75. Woltering JM, Duboule D. The origin of digits: expression patterns versus regulatory mechanisms. Dev Cell. 2010;18(4):526–32.

    CAS  PubMed  Google Scholar 

  76. Yokouchi Y, Sasaki H, Kuroiwa A. Homeobox gene expression correlated with the bifurcation process of limb cartilage development. Nature. 1991;353(6343):443–5.

    CAS  PubMed  Google Scholar 

  77. Nelson CE, Morgan BA, Burke AC, Laufer E, DiMambro E, Murtaugh LC, Gonzales E, Tessarollo L, Parada LF, Tabin C. Analysis of Hox gene expression in the chick limb bud. Development. 1996;122(5):1449–66.

    CAS  PubMed  Google Scholar 

  78. Kmita M, Fraudeau N, Herault Y, Duboule D. Serial deletions and duplications suggest a mechanism for the collinearity of Hoxd genes in limbs. Nature. 2002;420(6912):145–50.

    CAS  PubMed  Google Scholar 

  79. Dreyer SD, Naruse T, Morello R, Zabel B, Winterpacht A, Johnson RL, Lee B, Oberg KC. Lmx1b expression during joint and tendon formation: localization and evaluation of potential downstream targets. Gene Expr Patterns. 2004;4(4):397–405.

    CAS  PubMed  Google Scholar 

  80. Zeller R. It takes time to make a pinky: unexpected insights into how SHH patterns vertebrate digits. Sci STKE. 2004;2004(259):e53.

    Google Scholar 

  81. Harfe BD, Scherz PJ, Nissim S, Tian H, McMahon AP, Tabin CJ. Evidence for an expansion-based temporal Shh gradient in specifying vertebrate digit identities. Cell. 2004;118(4):517–28.

    CAS  PubMed  Google Scholar 

  82. Zhu J, Nakamura E, Nguyen MT, Bao X, Akiyama H, Mackem S. Uncoupling Sonic hedgehog control of pattern and expansion of the developing limb bud. Dev Cell. 2008;14(4):624–32.

    CAS  PubMed  Google Scholar 

  83. Yang Y, Drossopoulou G, Chuang PT, Duprez D, Marti E, Bumcrot D, Vargesson N, Clarke J, Niswander L, McMahon A, et al. Relationship between dose, distance and time in Sonic Hedgehog-mediated regulation of anteroposterior polarity in the chick limb. Development. 1997;124(21):4393–404.

    CAS  PubMed  Google Scholar 

  84. Towers M, Mahood R, Yin Y, Tickle C. Integration of growth and specification in chick wing digit-patterning. Nature. 2008; 452(7189):882–6.

    CAS  PubMed  Google Scholar 

  85. Sheth R, Marcon L, Bastida MF, Junco M, Quintana L, Dahn R, Kmita M, Sharpe J, Ros MA. Hox genes regulate digit patterning by controlling the wavelength of a Turing-type mechanism. Science. 2012;338(6113):1476–80.

    CAS  PubMed  Google Scholar 

  86. Turing AM. The chemical basis of morphogenesis. 1953. Bull Math Biol. 1990;52(1–2):153–97.

    CAS  PubMed  Google Scholar 

  87. Suzuki T, Hasso SM, Fallon JF. Unique SMAD1/5/8 activity at the phalanx-forming region determines digit identity. Proc Natl Acad Sci U S A. 2008;105(11):4185–90.

    CAS  PubMed Central  PubMed  Google Scholar 

  88. Montero JA, Lorda-Diez CI, Ganan Y, Macias D, Hurle JM. Activin/TGFbeta and BMP crosstalk determines digit chondrogenesis. Dev Biol. 2008;321(2):343–56.

    CAS  PubMed  Google Scholar 

  89. Dahn RD, Fallon JF. Interdigital regulation of digit identity and homeotic transformation by modulated BMP signaling. Science. 2000;289(5478):438–41.

    CAS  PubMed  Google Scholar 

  90. Chen Y, Knezevic V, Ervin V, Hutson R, Ward Y, Mackem S. Direct interaction with Hoxd proteins reverses Gli3-repressor function to promote digit formation downstream of Shh. Development. 2004;131(10):2339–47.

    CAS  PubMed  Google Scholar 

  91. Wang B, Fallon JF, Beachy PA. Hedgehog-regulated processing of Gli3 produces an anterior/posterior repressor gradient in the developing vertebrate limb. Cell. 2000;100(4):423–34.

    CAS  PubMed  Google Scholar 

  92. Drossopoulou G, Lewis KE, Sanz-Ezquerro JJ, Nikbakht N, McMahon AP, Hofmann C, Tickle C. A model for anteroposterior patterning of the vertebrate limb based on sequential long- and short-range Shh signalling and Bmp signalling. Development. 2000;127(7):1337–48.

    CAS  PubMed  Google Scholar 

  93. Rowe DA, Cairns JM, Fallon JF. Spatial and temporal patterns of cell death in limb bud mesoderm after apical ectodermal ridge removal. Dev Biol. 1982;93(1):83–91.

    CAS  PubMed  Google Scholar 

  94. Sanz-Ezquerro JJ, Tickle C. Fgf signaling controls the number of phalanges and tip formation in developing digits. Curr Biol. 2003;13(20):1830–6.

    CAS  PubMed  Google Scholar 

  95. Winkel A, Stricker S, Tylzanowski P, Seiffart V, Mundlos S, Gross G, Hoffmann A. Wnt-ligand-dependent interaction of TAK1 (TGF-beta-activated kinase-1) with the receptor tyrosine kinase Ror2 modulates canonical Wnt-signalling. Cell Signal. 2008; 20(11):2134–44.

    CAS  PubMed  Google Scholar 

  96. Witte F, Chan D, Economides AN, Mundlos S, Stricker S. Receptor tyrosine kinase-like orphan receptor 2 (ROR2) and Indian hedgehog regulate digit outgrowth mediated by the phalanx-forming region. Proc Natl Acad Sci U S A. 2010;107(32):14211–6.

    CAS  PubMed Central  PubMed  Google Scholar 

  97. Oberg KC. Review of the molecular development of the thumb: digit primera. Clin Orthop Relat Res. 2014;472(4):1101–5.

    PubMed  Google Scholar 

  98. Koshiba-Takeuchi K, Takeuchi JK, Arruda EP, Kathiriya IS, Mo R, Hui CC, Srivastava D, Bruneau BG. Cooperative and antagonistic interactions between Sall4 and Tbx5 pattern the mouse limb and heart. Nat Genet. 2006;38(2):175–83.

    CAS  PubMed  Google Scholar 

  99. Saint-Hilaire IG: Histoire g´en´erale et particuli `ere des anomalies de l’organisation chez l’homme et les animaux. Paris: J.B. Baillière; 1932.

    Google Scholar 

  100. Vargas AO, Fallon JF. Birds have dinosaur wings: the molecular evidence. J Exp Zool B Mol Dev Evol. 2005;304(1):86–90.

    PubMed  Google Scholar 

  101. Vargas AO, Kohlsdorf T, Fallon JF, Vandenbrooks J, Wagner GP. The evolution of HoxD-11 expression in the bird wing: insights from Alligator mississippiensis. PLoS One. 2008;3(10): e3325.

    PubMed Central  PubMed  Google Scholar 

  102. Villavicencio-Lorini P, Kuss P, Friedrich J, Haupt J, Farooq M, Turkmen S, Duboule D, Hecht J, Mundlos S. Homeobox genes d11-d13 and a13 control mouse autopod cortical bone and joint formation. J Clin Invest. 2010;120(6):1994–2004.

    CAS  PubMed Central  PubMed  Google Scholar 

  103. Hasson P, DeLaurier A, Bennett M, Grigorieva E, Naiche LA, Papaioannou VE, Mohun TJ, Logan MP. Tbx4 and tbx5 acting in connective tissue are required for limb muscle and tendon patterning. Dev Cell. 2010;18(1):148–56.

    CAS  PubMed Central  PubMed  Google Scholar 

  104. Casanova JC, Badia-Careaga C, Uribe V, Sanz-Ezquerro JJ. Bambi and Sp8 expression mark digit tips and their absence shows that chick wing digits 2 and 3 are truncated. PLoS One. 2012;7(12): e52781.

    CAS  PubMed Central  PubMed  Google Scholar 

  105. Casanova JC, Sanz-Ezquerro JJ. Digit morphogenesis: is the tip different? Dev Growth Differ. 2007;49(6):479–91.

    CAS  PubMed  Google Scholar 

  106. Kawakami Y, Esteban CR, Matsui T, Rodriguez-Leon J, Kato S, Izpisua Belmonte JC. Sp8 and Sp9, two closely related buttonhead-like transcription factors, regulate Fgf8 expression and limb outgrowth in vertebrate embryos. Development. 2004;131(19):4763–74.

    CAS  PubMed  Google Scholar 

  107. Haro E, Delgado I, Hunco M, Yamada Y, Mansouri A, Oberg KC, Ros MA: Sp6 and Sp8 transcription factors control AER formation and Dorsoventral Patterning in Limb Development. PLoS genetics. 2014;In Press.

    Google Scholar 

  108. Allan CH, Fleckman P, Fernandes RJ, Hager B, James J, Wisecarver Z, Satterstrom FK, Gutierrez A, Norman A, Pirrone A, et al. Tissue response and Msx1 expression after human fetal digit tip amputation in vitro. Wound Repair Regen. 2006;14(4): 398–404.

    PubMed  Google Scholar 

  109. Han M, Yang X, Farrington JE, Muneoka K. Digit regeneration is regulated by Msx1 and BMP4 in fetal mice. Development. 2003;130(21):5123–32.

    CAS  PubMed  Google Scholar 

  110. Yoon BS, Pogue R, Ovchinnikov DA, Yoshii I, Mishina Y, Behringer RR, Lyons KM. BMPs regulate multiple aspects of growth-plate chondrogenesis through opposing actions on FGF pathways. Development. 2006;133(23):4667–78.

    CAS  PubMed  Google Scholar 

  111. Cunningham TJ, Chatzi C, Sandell LL, Trainor PA, Duester G. Rdh10 mutants deficient in limb field retinoic acid signaling exhibit normal limb patterning but display interdigital webbing. Dev Dyn. 2011;240(5):1142–50.

    CAS  PubMed Central  PubMed  Google Scholar 

  112. Rodriguez-Leon J, Merino R, Macias D, Ganan Y, Santesteban E, Hurle JM. Retinoic acid regulates programmed cell death through BMP signalling. Nat Cell Biol. 1999;1(2):125–6.

    CAS  PubMed  Google Scholar 

  113. Weatherbee SD, Behringer RR, Rasweiler JJ, Niswander LA. Interdigital webbing retention in bat wings illustrates genetic changes underlying amniote limb diversification. Proc Natl Acad Sci U S A. 2006;103(41):15103–7.

    CAS  PubMed Central  PubMed  Google Scholar 

  114. Choi K. Hemangioblast development and regulation. Biochem Cell Biol. 1998;76(6):947–56.

    CAS  PubMed  Google Scholar 

  115. Nimmagadda S, Geetha Loganathan P, Huang R, Scaal M, Schmidt C, Christ B. BMP4 and noggin control embryonic blood vessel formation by antagonistic regulation of VEGFR-2 (Quek1) expression. Dev Biol. 2005;280(1):100–10.

    CAS  PubMed  Google Scholar 

  116. Park C, Afrikanova I, Chung YS, Zhang WJ, Arentson E, Fong Gh G, Rosendahl A, Choi K. A hierarchical order of factors in the generation of FLK1- and SCL-expressing hematopoietic and endothelial progenitors from embryonic stem cells. Development. 2004;131(11):2749–62.

    CAS  PubMed  Google Scholar 

  117. Shalaby F, Rossant J, Yamaguchi TP, Gertsenstein M, Wu XF, Breitman ML, Schuh AC. Failure of blood-island formation and vasculogenesis in Flk-1-deficient mice. Nature. 1995;376(6535): 62–6.

    CAS  PubMed  Google Scholar 

  118. Shalaby F, Ho J, Stanford WL, Fischer KD, Schuh AC, Schwartz L, Bernstein A, Rossant J. A requirement for Flk1 in primitive and definitive hematopoiesis and vasculogenesis. Cell. 1997;89(6): 981–90.

    CAS  PubMed  Google Scholar 

  119. Ferguson M, Byrnes C, Sun L, Marti G, Bonde P, Duncan M, Harmon JW. Wound healing enhancement: electroporation to address a classic problem of military medicine. World J Surg. 2005;29 Suppl 1:S55–9.

    PubMed  Google Scholar 

  120. Drake CJ. Embryonic and adult vasculogenesis. Birth Defects Res C Embryo Today. 2003;69(1):73–82.

    CAS  PubMed  Google Scholar 

  121. Moser M, Patterson C. Bone morphogenetic proteins and vascular differentiation: BMPing up vasculogenesis. Thromb Haemost. 2005;94(4):713–8.

    PubMed  Google Scholar 

  122. He L, Papoutsi M, Huang R, Tomarev SI, Christ B, Kurz H, Wilting J. Three different fates of cells migrating from somites into the limb bud. Anat Embryol (Berl). 2003;207(1):29–34.

    Google Scholar 

  123. Caplan AI. The vasculature and limb development. Cell Differ. 1985;16(1):1–11.

    CAS  PubMed  Google Scholar 

  124. Vargesson N. Vascularization of the developing chick limb bud: role of the TGFbeta signalling pathway. J Anat. 2003;202(1):93–103.

    CAS  PubMed Central  PubMed  Google Scholar 

  125. Deckers MM, van Bezooijen RL, van der Horst G, Hoogendam J, van Der Bent C, Papapoulos SE, Lowik CW. Bone morphogenetic proteins stimulate angiogenesis through osteoblast-derived vascular endothelial growth factor A. Endocrinology. 2002;143(4):1545–53.

    CAS  PubMed  Google Scholar 

  126. Hellstrom M, Phng LK, Hofmann JJ, Wallgard E, Coultas L, Lindblom P, Alva J, Nilsson AK, Karlsson L, Gaiano N, et al. Dll4 signalling through Notch1 regulates formation of tip cells during angiogenesis. Nature. 2007;445(7129):776–80.

    PubMed  Google Scholar 

  127. Siekmann AF, Lawson ND. Notch signalling limits angiogenic cell behaviour in developing zebrafish arteries. Nature. 2007;445(7129):781–4.

    CAS  PubMed  Google Scholar 

  128. Jones CA, Li DY. Common cues regulate neural and vascular patterning. Curr Opin Genet Dev. 2007;17(4):332–6.

    CAS  PubMed Central  PubMed  Google Scholar 

  129. Thurston G. Role of Angiopoietins and Tie receptor tyrosine kinases in angiogenesis and lymphangiogenesis. Cell Tissue Res. 2003;314(1):61–8.

    CAS  PubMed  Google Scholar 

  130. Krebs LT, Xue Y, Norton CR, Shutter JR, Maguire M, Sundberg JP, Gallahan D, Closson V, Kitajewski J, Callahan R, et al. Notch signaling is essential for vascular morphogenesis in mice. Genes Dev. 2000;14(11):1343–52.

    CAS  PubMed Central  PubMed  Google Scholar 

  131. Tamura K, Amano T, Satoh T, Saito D, Yonei-Tamura S, Yajima H. Expression of rigf, a member of avian VEGF family, correlates with vascular patterning in the developing chick limb bud. Mech Dev. 2003;120(2):199–209.

    CAS  PubMed  Google Scholar 

  132. Betsholtz C, Lindblom P, Gerhardt H. Role of pericytes in vascular morphogenesis. EXS. 2005;94:115–25.

    PubMed  Google Scholar 

  133. Ribes V, Otto DM, Dickmann L, Schmidt K, Schuhbaur B, Henderson C, Blomhoff R, Wolf CR, Tickle C, Dolle P. Rescue of cytochrome P450 oxidoreductase (Por) mouse mutants reveals functions in vasculogenesis, brain and limb patterning linked to retinoic acid homeostasis. Dev Biol. 2007;303(1):66–81.

    CAS  PubMed  Google Scholar 

  134. Ribes V, Fraulob V, Petkovich M, Dolle P. The oxidizing enzyme CYP26a1 tightly regulates the availability of retinoic acid in the gastrulating mouse embryo to ensure proper head development and vasculogenesis. Dev Dyn. 2007;236(3):644–53.

    CAS  PubMed  Google Scholar 

  135. Rodriguez-Niedenfuhr M, Burton GJ, Deu J, Sanudo JR. Development of the arterial pattern in the upper limb of staged human embryos: normal development and anatomic variations. J Anat. 2001;199(Pt 4):407–17.

    CAS  PubMed Central  PubMed  Google Scholar 

  136. Mrazkova O. Ontogenesis of arterial trunks in the human fore-arm. Folia Morphol (Praha). 1973;21(2):193–6.

    CAS  Google Scholar 

  137. Kawakami Y, Rodriguez-Leon J, Belmonte JC. The role of TGFbetas and Sox9 during limb chondrogenesis. Curr Opin Cell Biol. 2006;18(6):723–9.

    CAS  PubMed  Google Scholar 

  138. Akiyama H, Chaboissier MC, Martin JF, Schedl A, de Crombrugghe B. The transcription factor Sox9 has essential roles in successive steps of the chondrocyte differentiation pathway and is required for expression of Sox5 and Sox6. Genes Dev. 2002;16(21):2813–28.

    CAS  PubMed Central  PubMed  Google Scholar 

  139. Lefebvre V, Li P, de Crombrugghe B. A new long form of Sox5 (L-Sox5), Sox6 and Sox9 are coexpressed in chondrogenesis and cooperatively activate the type II collagen gene. EMBO J. 1998;17(19):5718–33.

    CAS  PubMed Central  PubMed  Google Scholar 

  140. Karsenty G. Transcriptional control of skeletogenesis. Annu Rev Genomics Hum Genet. 2008;9:183–96.

    CAS  PubMed  Google Scholar 

  141. Zou H, Wieser R, Massague J, Niswander L. Distinct roles of type I bone morphogenetic protein receptors in the formation and differentiation of cartilage. Genes Dev. 1997;11(17):2191–203.

    CAS  PubMed Central  PubMed  Google Scholar 

  142. Pizette S, Niswander L. BMPs are required at two steps of limb chondrogenesis: formation of prechondrogenic condensations and their differentiation into chondrocytes. Dev Biol. 2000;219(2): 237–49.

    CAS  PubMed  Google Scholar 

  143. Yoon BS, Ovchinnikov DA, Yoshii I, Mishina Y, Behringer RR, Lyons KM. Bmpr1a and Bmpr1b have overlapping functions and are essential for chondrogenesis in vivo. Proc Natl Acad Sci U S A. 2005;102(14):5062–7.

    CAS  PubMed Central  PubMed  Google Scholar 

  144. Bandyopadhyay A, Yadav PS, Prashar P. BMP signaling in development and diseases: a pharmacological perspective. Biochem Pharmacol. 2013;85(7):857–64.

    CAS  PubMed  Google Scholar 

  145. Weston AD, Rosen V, Chandraratna RA, Underhill TM. Regulation of skeletal progenitor differentiation by the BMP and retinoid signaling pathways. J Cell Biol. 2000;148(4):679–90.

    CAS  PubMed Central  PubMed  Google Scholar 

  146. Weston AD, Chandraratna RA, Torchia J, Underhill TM. Requirement for RAR-mediated gene repression in skeletal progenitor differentiation. J Cell Biol. 2002;158(1):39–51.

    CAS  PubMed Central  PubMed  Google Scholar 

  147. Dranse HJ, Sampaio AV, Petkovich M, Underhill TM. Genetic deletion of Cyp26b1 negatively impacts limb skeletogenesis by inhibiting chondrogenesis. J Cell Sci. 2011;124(Pt 16):2723–34.

    CAS  PubMed  Google Scholar 

  148. Hoffman LM, Garcha K, Karamboulas K, Cowan MF, Drysdale LM, Horton WA, Underhill TM. BMP action in skeletogenesis involves attenuation of retinoid signaling. J Cell Biol. 2006;174(1): 101–13.

    CAS  PubMed Central  PubMed  Google Scholar 

  149. Gray DJ, Gardner E, O’Rahilly R. The prenatal development of the skeleton and joints of the human hand. Am J Anat. 1957;101(2):169–223.

    CAS  PubMed  Google Scholar 

  150. Shubin NH, Alberch P. A morphogenetic approach to the origin and basic organization of the tetrapod limb. In: Evolutionary Biology. New York: Plenum Press; 1986. p. 319–87.

    Google Scholar 

  151. Hinchliffe JR, Johnson DR. The development of the vertebrate limb. Oxford: Clarendon; 1980.

    Google Scholar 

  152. Kim IS, Otto F, Zabel B, Mundlos S. Regulation of chondrocyte differentiation by Cbfa1. Mech Dev. 1999;80(2):159–70.

    CAS  PubMed  Google Scholar 

  153. Nakashima K, Zhou X, Kunkel G, Zhang Z, Deng JM, Behringer RR, de Crombrugghe B. The novel zinc finger-containing transcription factor osterix is required for osteoblast differentiation and bone formation. Cell. 2002;108(1):17–29.

    CAS  PubMed  Google Scholar 

  154. Yang X, Matsuda K, Bialek P, Jacquot S, Masuoka HC, Schinke T, Li L, Brancorsini S, Sassone-Corsi P, Townes TM, et al. ATF4 is a substrate of RSK2 and an essential regulator of osteoblast biology; implication for Coffin-Lowry Syndrome. Cell. 2004; 117(3):387–98.

    CAS  PubMed  Google Scholar 

  155. Mackie EJ, Ahmed YA, Tatarczuch L, Chen KS, Mirams M. Endochondral ossification: how cartilage is converted into bone in the developing skeleton. Int J Biochem Cell Biol. 2008; 40(1):46–62.

    CAS  PubMed  Google Scholar 

  156. Noback CR, Robertson GG. Sequences of appearance of ossification centers in the human skeleton during the first five prenatal months. Am J Anat. 1951;89(1):1–28.

    CAS  PubMed  Google Scholar 

  157. Stuart HC, Pyle SI, Cornoni J, Reed RB. Onsets, completions and spans of ossification in the 29 bone growth centers of the hand and wrist. Pediatrics. 1962;29:237–49.

    CAS  PubMed  Google Scholar 

  158. Hartmann C, Tabin CJ. Wnt-14 plays a pivotal role in inducing synovial joint formation in the developing appendicular skeleton. Cell. 2001;104(3):341–51.

    CAS  PubMed  Google Scholar 

  159. Storm EE, Kingsley DM. GDF5 coordinates bone and joint formation during digit development. Dev Biol. 1999;209(1):11–27.

    CAS  PubMed  Google Scholar 

  160. Dalgleish AE. Development of the limbs of the mouse. Stanford: Stanford University; 1964.

    Google Scholar 

  161. Craig FM, Bayliss MT, Bentley G, Archer CW. A role for hyaluronan in joint development. J Anat. 1990;171(4):17–23.

    CAS  PubMed Central  PubMed  Google Scholar 

  162. Nowlan NC, Sharpe J, Roddy KA, Prendergast PJ, Murphy P. Mechanobiology of embryonic skeletal development: Insights from animal models. Birth Defects Res C Embryo Today. 2010;90(3):203–13.

    CAS  PubMed  Google Scholar 

  163. Khan IM, Redman SN, Williams R, Dowthwaite GP, Oldfield SF, Archer CW. The development of synovial joints. Curr Top Dev Biol. 2007;79:1–36.

    CAS  PubMed  Google Scholar 

  164. Pacifici M, Koyama E, Iwamoto M. Mechanisms of synovial joint and articular cartilage formation: recent advances, but many lingering mysteries. Birth Defects Res C Embryo Today. 2005;75(3):237–48.

    CAS  PubMed  Google Scholar 

  165. Tozer S, Duprez D. Tendon and ligament: development, repair and disease. Birth Defects Res C Embryo Today. 2005;75(3):226–36.

    CAS  PubMed  Google Scholar 

  166. Mitrovic D. Development of the diarthrodial joints in the rat embryo. Am J Anat. 1978;151(4):475–85.

    CAS  PubMed  Google Scholar 

  167. Sharma K, Izpisua Belmonte JC. Development of the limb neuromuscular system. Curr Opin Cell Biol. 2001;13(2):204–10.

    CAS  PubMed  Google Scholar 

  168. Schweitzer R, Chyung JH, Murtaugh LC, Brent AE, Rosen V, Olson EN, Lassar A, Tabin CJ. Analysis of the tendon cell fate using Scleraxis, a specific marker for tendons and ligaments. Development. 2001;128(19):3855–66.

    CAS  PubMed  Google Scholar 

  169. Ros MA, Rivero FB, Hinchliffe JR, Hurle JM. Immunohistological and ultrastructural study of the developing tendons of the avian foot. Anat Embryol (Berl). 1995;192(6):483–96.

    CAS  Google Scholar 

  170. Kardon G. Muscle and tendon morphogenesis in the avian hind limb. Development. 1998;125(20):4019–32.

    CAS  PubMed  Google Scholar 

  171. Edom-Vovard F, Duprez D. Signals regulating tendon formation during chick embryonic development. Dev Dyn. 2004;229(3): 449–57.

    CAS  PubMed  Google Scholar 

  172. Murphy M, Kardon G. Origin of vertebrate limb muscle: the role of progenitor and myoblast populations. Curr Top Dev Biol. 2011;96:1–32.

    CAS  PubMed  Google Scholar 

  173. Williams BA, Ordahl CP. Pax-3 expression in segmental mesoderm marks early stages in myogenic cell specification. Development. 1994;120(4):785–96.

    CAS  PubMed  Google Scholar 

  174. Buckingham M, Bajard L, Chang T, Daubas P, Hadchouel J, Meilhac S, Montarras D, Rocancourt D, Relaix F. The formation of skeletal muscle: from somite to limb. J Anat. 2003;202(1): 59–68.

    PubMed Central  PubMed  Google Scholar 

  175. Sze LY, Lee KK, Webb SE, Li Z, Paulin D. Migration of myogenic cells from the somites to the fore-limb buds of developing mouse embryos. Dev Dyn. 1995;203(3):324–36.

    CAS  PubMed  Google Scholar 

  176. Bober E, Franz T, Arnold HH, Gruss P, Tremblay P. Pax-3 is required for the development of limb muscles: a possible role for the migration of dermomyotomal muscle progenitor cells. Development. 1994;120(3):603–12.

    CAS  PubMed  Google Scholar 

  177. Dietrich S, Abou-Rebyeh F, Brohmann H, Bladt F, Sonnenberg-Riethmacher E, Yamaai T, Lumsden A, Brand-Saberi B, Birchmeier C. The role of SF/HGF and c-Met in the development of skeletal muscle. Development. 1999;126(8):1621–9.

    CAS  PubMed  Google Scholar 

  178. Bladt F, Riethmacher D, Isenmann S, Aguzzi A, Birchmeier C. Essential role for the c-met receptor in the migration of myogenic precursor cells into the limb bud. Nature. 1995;376(6543):768–71.

    CAS  PubMed  Google Scholar 

  179. Brand-Saberi B, Muller TS, Wilting J, Christ B, Birchmeier C. Scatter factor/hepatocyte growth factor (SF/HGF) induces emigration of myogenic cells at interlimb level in vivo. Dev Biol. 1996;179(1):303–8.

    CAS  PubMed  Google Scholar 

  180. Scaal M, Bonafede A, Dathe V, Sachs M, Cann G, Christ B, Brand-Saberi B. SF/HGF is a mediator between limb patterning and muscle development. Development. 1999;126(21):4885–93.

    CAS  PubMed  Google Scholar 

  181. Epstein JA, Shapiro DN, Cheng J, Lam PY, Maas RL. Pax3 modulates expression of the c-Met receptor during limb muscle development. Proc Natl Acad Sci U S A. 1996;93(9):4213–8.

    CAS  PubMed Central  PubMed  Google Scholar 

  182. Schmidt C, Bladt F, Goedecke S, Brinkmann V, Zschiesche W, Sharpe M, Gherardi E, Birchmeier C. Scatter factor/hepatocyte growth factor is essential for liver development. Nature. 1995;373(6516):699–702.

    CAS  PubMed  Google Scholar 

  183. Schafer K, Braun T. Early specification of limb muscle precursor cells by the homeobox gene Lbx1h. Nat Genet. 1999;23(2):213–6.

    CAS  PubMed  Google Scholar 

  184. Tajbakhsh S, Buckingham ME. Mouse limb muscle is determined in the absence of the earliest myogenic factor myf-5. Proc Natl Acad Sci U S A. 1994;91(2):747–51.

    CAS  PubMed Central  PubMed  Google Scholar 

  185. Ontell M, Kozeka K. The organogenesis of murine striated muscle: a cytoarchitectural study. Am J Anat. 1984;171(2):133–48.

    CAS  PubMed  Google Scholar 

  186. Otto A, Collins-Hooper H, Patel K. The origin, molecular regulation and therapeutic potential of myogenic stem cell populations. J Anat. 2009;215(5):477–97.

    CAS  PubMed Central  PubMed  Google Scholar 

  187. Dieu T, Newgreen D. Chicken wings and the brachial plexus. Neurol Res. 2007;29(3):225–30.

    PubMed  Google Scholar 

  188. Wehrle-Haller B, Koch M, Baumgartner S, Spring J, Chiquet M. Nerve-dependent and -independent tenascin expression in the developing chick limb bud. Development. 1991;112(2):627–37.

    CAS  PubMed  Google Scholar 

  189. Swanson GJ, Lewis J. Sensory nerve routes in chick wing buds deprived of motor innervation. J Embryol Exp Morphol. 1986;95:37–52.

    CAS  PubMed  Google Scholar 

  190. Swanson GJ. Paths taken sensory nerve fibres in aneural chick wing buds. J Embryol Exp Morphol. 1985;86:109–24.

    CAS  PubMed  Google Scholar 

  191. Martin P, Khan A, Lewis J. Cutaneous nerves of the embryonic chick wing do not develop in regions denuded of ectoderm. Development. 1989;106(2):335–46.

    CAS  PubMed  Google Scholar 

  192. Lewis J, Chevallier A, Kieny M, Wolpert L. Muscle nerve branches do not develop in chick wings devoid of muscle. J Embryol Exp Morphol. 1981;64:211–32.

    CAS  PubMed  Google Scholar 

  193. Polleux F, Ince-Dunn G, Ghosh A. Transcriptional regulation of vertebrate axon guidance and synapse formation. Nat Rev Neurosci. 2007;8(5):331–40.

    CAS  PubMed  Google Scholar 

  194. Dasen JS, Jessell TM. Hox networks and the origins of motor neuron diversity. Curr Top Dev Biol. 2009;88:169–200.

    CAS  PubMed  Google Scholar 

  195. Kao TJ, Law C, Kania A. Eph and ephrin signaling: lessons learned from spinal motor neurons. Semin Cell Dev Biol. 2012;23(1):83–91.

    CAS  PubMed  Google Scholar 

  196. Dasen JS. Transcriptional networks in the early development of sensory-motor circuits. Curr Top Dev Biol. 2009;87:119–48.

    PubMed  Google Scholar 

  197. Manske PR, Oberg KC. Classification and developmental biology of congenital anomalies of the hand and upper extremity. J Bone Joint Surg Am. 2009;91 Suppl 4:3–18.

    PubMed  Google Scholar 

  198. Tonkin MA, Oberg KC. Congenital hand I—embryology, classification, and principles. In: Cheng J, Neligan PC, editors. Plastic surgery, vol 6: hand and upper extremity. 3rd ed. New York: Elsevier; 2012. p. 526–47.

    Google Scholar 

  199. Saint-Hilaire IG. Propositions sur la monstruosité. Paris: Imp. Didot le Jeune; 1829.

    Google Scholar 

  200. Saint-Hilaire IG. Histoire générale et particuli ère des anomalies de l’organisation chez l’homme et les animaux. Paris: J.B. Baillière; 1932.

    Google Scholar 

  201. Swanson AB. A classification for congenital malformations of the hand. N J Bull Acad Med. 1964;10:166–9.

    Google Scholar 

  202. Lösch GM, Buck-Gramcko D, Cihak R, Sharader M, Seichert V. An attempt to classify the malformations of the hand based on morphogenetic criteria. Chir Plastica. 1984;8(1):18.

    Google Scholar 

  203. Temtamy SA. Genetic factors in hand malformations. Baltimore: Johns Hopkins University; 1966.

    Google Scholar 

  204. Temtamy SA, McKusick VA. The genetics of hand malformations. Birth Defects Orig Artic Ser. 1978;14(3):i–619.

    CAS  PubMed  Google Scholar 

  205. Kay H. A proposed international terminology for the classification of congenital limb deficiencies. ICIB/JACPOC. 1974;13(7):1–16.

    Google Scholar 

  206. Kelikian H. Congenital deformities of the hand and forearm. Philadelphia: WB Saunders Company; 1974.

    Google Scholar 

  207. Knight SL, Kay SPJ. Classification of congenital anomalies. In: Gupta A, Kay SPJ, Scheker LR, editors. The growing hand. London: Harcourt; 2000. p. 125–35.

    Google Scholar 

  208. Tonkin MA. Description of congenital hand anomalies: a personal view. J Hand Surg Br. 2006;31(5):489–97.

    CAS  PubMed  Google Scholar 

  209. Oberg KC, Feenstra JM, Manske PR, Tonkin MA. Developmental biology and classification of congenital anomalies of the hand and upper extremity. J Hand Surg Am. 2010;35(12):2066–76.

    PubMed  Google Scholar 

  210. Ogino T. JSSH CHCot: modified IFSSH classification. J Jpn Soc Surg Hand. 2000;17:353–65.

    Google Scholar 

  211. Tonkin MA, Tolerton SK, Quick TJ, Harvey I, Lawson RD, Smith NC, Oberg KC. Classification of congenital anomalies of the hand and upper limb: development and assessment of a new system. J Hand Surg Am. 2013;13:10.

    Google Scholar 

  212. Ezaki M, Baek GH, Horii E, Hovius SE. Classification of congenital hand and upper limb anomalies. In: Ezaki M, editor. Scientific committee on congenital conditions, vol. 14. IFSSH Ezine; 2014. p. 4.

    Google Scholar 

  213. Ekblom AG, Laurell T, Arner M. Epidemiology of congenital upper limb anomalies in Stockholm, Sweden, 1997 to 2007: application of the Oberg, Manske, and Tonkin classification. J Hand Surg. 2014;39(2):237–48.

    Google Scholar 

  214. Oberg KC, Feenstra JM, Manske PR, Tonkin MA. A new classification of congenital anomalies of the hand and upper limb. IFSSH Ezine. 2011;1(2):3.

    Google Scholar 

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Acknowledgements

The authors would like to thank Charmaine Pira for suggestions, insight, and careful review of this manuscript.

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Authors and Affiliations

  1. Department of Molecular and Cellular Anatomy, Instituto de Biomedicina y Biotecnologia de Cantabria (IBBTEC), CSIC-SODERCAN-Universidad de Cantabria, C/Albert Einstein, 22. 39011 (PTCAN), Santander, Cantabria 39, Spain

    Carlos Garrido-Allepuz Herrera Ph.D.

  2. Department of Hand Surgery and Peripheral Nerve Surgery, Royal North Shore Hospital, The Children’s Hospital at Westmead, University of Sydney, Sydney, NSW, 2065, Australia

    Michael A. Tonkin M.B.B.S., M.D., F.R.A.C.S., F.R.C.S. (Ed Orth)

  3. Department of Pathology and Human Anatomy, Loma Linda University Medical Center, Molecular Embryopathy Laboratory, 24785 Stewart St., Loma Linda, CA, 92354, USA

    Kerby C. Oberg M.D., Ph.D.

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  1. Carlos Garrido-Allepuz Herrera Ph.D.
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  3. Kerby C. Oberg M.D., Ph.D.
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  1. Fletcher Allen Health Care and Vermont Children’s Hospital, Departments of Surgery and Pediatrics, University of Vermont School of Medicine, Burlington, Vermont, USA

    Donald R. Laub Jr.

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Herrera, C.GA., Tonkin, M.A., Oberg, K.C. (2015). Embryology and Classification of Congenital Upper Limb Anomalies. In: Laub Jr., D. (eds) Congenital Anomalies of the Upper Extremity. Springer, Boston, MA. https://doi.org/10.1007/978-1-4899-7504-1_1

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