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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: KS GA, Sheker LR, editors. The growing hand: diagnosis and management of the upper extremity in children. London: CV Mosby; 2000. p. 25–32.

    Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  4. Moreau C, Caldarelli P, Rocancourt D, Roussel J, Denans N, Pourquie O, et al. Timed collinear activation of hox genes during gastrulation controls the avian forelimb position. Curr Biol. 2019;29(1):35–50.e34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  6. Gros J, Tabin CJ. Vertebrate limb bud formation is initiated by localized epithelial-to-mesenchymal transition. Science. 2014;343(6176):1253–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. 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.

    Article  CAS  PubMed  Google Scholar 

  8. Ohuchi H, Nakagawa T, Yamamoto A, Araga A, Ohata T, Ishimaru Y, 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.

    Article  CAS  PubMed  Google Scholar 

  9. 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.

    Article  CAS  PubMed  Google Scholar 

  10. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Narita T, Nishimatsu S, Wada N, Nohno T. A Wnt3a variant participates in chick apical ectodermal ridge formation: distinct biological activities of Wnt3a splice variants in chick limb development. Dev Growth Differ. 2007;49(6):493–501.

    Article  CAS  PubMed  Google Scholar 

  13. Wilkie AO, Patey SJ, Kan SH, van den Ouweland AM, Hamel BC. FGFs, their receptors, and human limb malformations: clinical and molecular correlations. Am J Med Genet. 2002;112(3):266–78.

    Article  PubMed  Google Scholar 

  14. 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.

    Article  CAS  PubMed  Google Scholar 

  15. Soshnikova N, Zechner D, Huelsken J, Mishina Y, Behringer RR, Taketo MM, et al. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Jin L, Wu J, Bellusci S, Zhang J-S. Fibroblast growth factor 10 and vertebrate limb development. Front Genet. 2019;9(705)

    Google Scholar 

  17. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  19. 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.

    Article  CAS  PubMed  Google Scholar 

  20. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. 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.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  25. Fallon JF, Kelley RO. Ultrastructural 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(1):223–32.

    CAS  PubMed  Google Scholar 

  26. 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 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  32. 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.

    Article  CAS  PubMed  Google Scholar 

  33. 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.

    Article  CAS  PubMed  Google Scholar 

  34. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  37. 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.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  42. Rosello-Diez A, Arques CG, Delgado I, Giovinazzo G, Torres M. Diffusible signals and epigenetic timing cooperate in late proximo-distal limb patterning. Development. 2014;141(7):1534–43.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  44. 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.

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  46. Yakushiji-Kaminatsui N, Kondo T, Hironaka KI, Sharif J, Endo TA, Nakayama M, et al. Variant PRC1 competes with retinoic acid-related signals to repress Meis2 in the mouse distal forelimb bud. Development. 2018;145(19)

    Google Scholar 

  47. Knezevic V, De Santo R, Schughart K, Huffstadt U, Chiang C, Mahon KA, et al. 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.

    Article  CAS  PubMed  Google Scholar 

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

    Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  51. 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.

    Article  CAS  PubMed  Google Scholar 

  52. 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.

    Article  CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  54. 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.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Li D, Sakuma R, Vakili NA, Mo R, Puviindran V, Deimling S, et al. Formation of proximal and anterior limb skeleton requires early function of Irx3 and Irx5 and is negatively regulated by Shh signaling. Dev Cell. 2014;29(2):233–40.

    Article  CAS  PubMed  Google Scholar 

  59. 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.

    Article  CAS  PubMed  Google Scholar 

  60. 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.

    Article  PubMed  Google Scholar 

  61. Galli A, Robay D, Osterwalder M, Bao X, Benazet JD, Tariq M, et al. Distinct roles of Hand2 in initiating polarity and posterior Shh expression during the onset of mouse limb bud development. PLoS Genet. 2010;6(4):e1000901.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  63. 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.

    Article  CAS  PubMed  Google Scholar 

  64. 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.

    Article  CAS  PubMed  Google Scholar 

  65. 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.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  68. 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.

    Article  CAS  PubMed  Google Scholar 

  69. 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.

    Article  CAS  PubMed  Google Scholar 

  70. 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.

    Article  CAS  PubMed  Google Scholar 

  71. 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.

    Article  CAS  PubMed  Google Scholar 

  72. 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.

    Article  CAS  PubMed  Google Scholar 

  73. 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.

    Article  CAS  PubMed  Google Scholar 

  74. 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.

    Article  CAS  PubMed  Google Scholar 

  75. Haro E, Watson BA, Feenstra JM, Tegeler L, Pira CU, Mohan S, et al. Lmx1b-targeted cis-regulatory modules involved in limb dorsalization. Development. 2017;144(11):2009–20.

    CAS  PubMed  Google Scholar 

  76. 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.

    Article  CAS  PubMed  Google Scholar 

  77. 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.

    Article  CAS  PubMed  Google Scholar 

  78. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  80. Watson BA, Feenstra JM, Van Arsdale JM, Rai-Bhatti KS, Kim DJH, Coggins AS, et al. LHX2 mediates the FGF-to-SHH regulatory loop during limb development. J Dev Biol. 2018;6(2):13. 01-19

    Article  CAS  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Pickering J, Rich CA, Stainton H, Aceituno C, Chinnaiya K, Saiz-Lopez P, Ros MA, Towers M. An intrinsic cell cycle timer terminates limb bud outgrowth. Elife. 2018;7

    Google Scholar 

  83. 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.

    Article  CAS  PubMed  Google Scholar 

  84. 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.

    Article  CAS  Google Scholar 

  85. Petit F, Sears KE, Ahituv N. Limb development: a paradigm of gene regulation. Nat Rev Genet. 2017;18(4):245–58.

    Article  CAS  PubMed  Google Scholar 

  86. Williamson I, Kane L, Devenney PS, Flyamer IM, Anderson E, Kilanowski F, et al. Developmentally regulated Shh expression is robust to TAD perturbations. Development. 2019:146(19).

    Google Scholar 

  87. Lettice LA, Horikoshi T, Heaney SJ, van Baren MJ, van der Linde HC, Breedveld GJ, et al. Disruption of a long-range cis-acting regulator for Shh causes preaxial polydactyly. Proc Natl Acad Sci U S A. 2002;99(11):7548–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Sagai T, Hosoya M, Mizushina Y, Tamura M, Shiroishi T. Elimination of a long-range cis-regulatory module causes complete loss of limb-specific Shh expression and truncation of the mouse limb. Development. 2005;132(4):797–803.

    Article  CAS  PubMed  Google Scholar 

  89. Williamson I, Lettice LA, Hill RE, Bickmore WA. Shh and ZRS enhancer colocalisation is specific to the zone of polarising activity. Development. 2016;143(16):2994–3001.

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Potuijt JWP, Galjaard RH, van der Spek PJ, van Nieuwenhoven CA, Ahituv N, Oberg KC, et al. A multidisciplinary review of triphalangeal thumb. J Hand Surg Eur Vol. 2019;44(1):59–68.

    Article  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  92. Marinic M, Aktas T, Ruf S, Spitz F. An integrated holo-enhancer unit defines tissue and gene specificity of the Fgf8 regulatory landscape. Dev Cell. 2013;24(5):530–42.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  95. Nelson CE, Morgan BA, Burke AC, Laufer E, DiMambro E, Murtaugh LC, et al. Analysis of Hox gene expression in the chick limb bud. Development. 1996;122(5):1449–66.

    Article  CAS  PubMed  Google Scholar 

  96. 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.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  98. Zeller R: It takes time to make a pinky: unexpected insights into how SHH patterns vertebrate digits. Sci STKE 2004, 2004(259):pe53.

    Google Scholar 

  99. 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.

    Article  CAS  PubMed  Google Scholar 

  100. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Yang Y, Drossopoulou G, Chuang PT, Duprez D, Marti E, Bumcrot D, 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.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Turing AM. The chemical basis of morphogenesis. Phil Trans R Soc Lond B. 1952;237:37–72.

    Article  Google Scholar 

  105. Raspopovic J, Marcon L, Russo L, Sharpe J. Modeling digits. Digit patterning is controlled by a Bmp-Sox9-Wnt Turing network modulated by morphogen gradients. Science. 2014;345(6196):566–70.

    Article  CAS  PubMed  Google Scholar 

  106. Newman SA, Glimm T, Bhat R. The vertebrate limb: an evolving complex of self-organizing systems. Prog Biophys Mol Biol. 2018;137:12–24.

    Article  PubMed  Google Scholar 

  107. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. 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.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  110. 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.

    Article  CAS  PubMed  Google Scholar 

  111. 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.

    Article  CAS  PubMed  Google Scholar 

  112. Drossopoulou G, Lewis KE, Sanz-Ezquerro JJ, Nikbakht N, McMahon AP, Hofmann C, et al. 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.

    Article  CAS  PubMed  Google Scholar 

  113. 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.

    Article  CAS  PubMed  Google Scholar 

  114. 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.

    Article  CAS  PubMed  Google Scholar 

  115. Winkel A, Stricker S, Tylzanowski P, Seiffart V, Mundlos S, Gross G, et al. 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.

    Article  CAS  PubMed  Google Scholar 

  116. 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 USA. 2010;107(32):14211–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. 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.

    Article  CAS  PubMed  Google Scholar 

  118. Bastida MF, Perez-Gomez R, Trofka A, Zhu J, Rada-Iglesias A, Sheth R, et al. The formation of the thumb requires direct modulation of Gli3 transcription by Hoxa13. Proc Natl Acad Sci U S A. 2020;117(2):1090–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Montavon T, Le Garrec JF, Kerszberg M, Duboule D. Modeling Hox gene regulation in digits: reverse collinearity and the molecular origin of thumbness. Genes Dev. 2008;22(3):346–59.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  121. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  126. 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.

    Article  CAS  PubMed  Google Scholar 

  127. Haro E, Delgado I, Junco M, Yamada Y, Mansouri A, Oberg KC, et al. Sp6 and Sp8 transcription factors control AER formation and dorsal-ventral patterning in limb development. PLoS Genet. 2014;10(8):e1004468.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  Google Scholar 

  129. 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.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  131. Murgai A, Altmeyer S, Wiegand S, Tylzanowski P, Stricker S. Cooperation of BMP and IHH signaling in interdigital cell fate determination. PLoS One. 2018;13(5):e0197535.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. 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.

    Article  CAS  PubMed  Google Scholar 

  134. 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 USA. 2006;103(41):15103–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  136. Craig MP, Sumanas S. ETS transcription factors in embryonic vascular development. Angiogenesis. 2016;19(3):275–85.

    Article  PubMed  PubMed Central  Google Scholar 

  137. Koyano-Nakagawa N, Garry DJ. Etv2 as an essential regulator of mesodermal lineage development. Cardiovasc Res. 2017;113(11):1294–306.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Lee D, Park C, Lee H, Lugus JJ, Kim SH, Arentson E, et al. ER71 acts downstream of BMP, Notch, and Wnt signaling in blood and vessel progenitor specification. Cell Stem Cell. 2008;2(5):497–507.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Park C, Afrikanova I, Chung YS, Zhang WJ, Arentson E, Fong Gh G, et al. 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.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  142. Zimna A, Kurpisz M. Hypoxia-inducible factor-1 in physiological and pathophysiological angiogenesis: applications and therapies. Biomed Res Int. 2015;2015:549412.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    PubMed  Google Scholar 

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

    Article  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  153. Krebs LT, Xue Y, Norton CR, Shutter JR, Maguire M, Sundberg JP, et al. Notch signaling is essential for vascular morphogenesis in mice. Genes Dev. 2000;14(11):1343–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. 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.

    Article  CAS  PubMed  Google Scholar 

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

    Google Scholar 

  156. Wolf K, Hu H, Isaji T, Dardik A. Molecular identity of arteries, veins, and lymphatics. J Vasc Surg. 2019;69(1):253–62.

    Article  PubMed  Google Scholar 

  157. Pawlikowski B, Wragge J, Siegenthaler JA. Retinoic acid signaling in vascular development. Genesis. 2019;57(7–8):e23287.

    Article  PubMed  PubMed Central  Google Scholar 

  158. Bohnsack BL, Lai L, Dolle P, Hirschi KK. Signaling hierarchy downstream of retinoic acid that independently regulates vascular remodeling and endothelial cell proliferation. Genes Dev. 2004;18(11):1345–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Ribes V, Otto DM, Dickmann L, Schmidt K, Schuhbaur B, Henderson C, et al. 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.

    Article  CAS  PubMed  Google Scholar 

  160. 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.

    Article  CAS  PubMed  Google Scholar 

  161. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  Google Scholar 

  163. Marin-Llera JC, Garciadiego-Cazares D, Chimal-Monroy J. Understanding the cellular and molecular mechanisms that control early cell fate decisions during appendicular skeletogenesis. Front Genet. 2019;10:977.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. 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.

    Article  CAS  PubMed  Google Scholar 

  165. Amarilio R, Viukov SV, Sharir A, Eshkar-Oren I, Johnson RS, Zelzer E. HIF1alpha regulation of Sox9 is necessary to maintain differentiation of hypoxic prechondrogenic cells during early skeletogenesis. Development. 2007;134(21):3917–28.

    Article  CAS  PubMed  Google Scholar 

  166. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  Google Scholar 

  168. Bhattaram P, Penzo-Mendez A, Kato K, Bandyopadhyay K, Gadi A, Taketo MM, et al. SOXC proteins amplify canonical WNT signaling to secure nonchondrocytic fates in skeletogenesis. J Cell Biol. 2014;207(5):657–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Diaz-Hernandez ME, Bustamante M, Galvan-Hernandez CI, Chimal-Monroy J. Irx1 and Irx2 are coordinately expressed and regulated by retinoic acid, TGFbeta and FGF signaling during chick hindlimb development. PLoS One. 2013;8(3):e58549.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. 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.

    Article  CAS  PubMed  Google Scholar 

  172. 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 USA. 2005;102(14):5062–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  174. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. 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.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. 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.

    Article  CAS  PubMed  Google Scholar 

  179. 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.

    Chapter  Google Scholar 

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

    Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  182. 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.

    Article  CAS  PubMed  Google Scholar 

  183. Yang X, Matsuda K, Bialek P, Jacquot S, Masuoka HC, Schinke T, 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.

    Article  CAS  PubMed  Google Scholar 

  184. 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.

    Article  CAS  PubMed  Google Scholar 

  185. 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.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  187. 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.

    Article  CAS  PubMed  Google Scholar 

  188. Decker RS, Koyama E, Pacifici M. Genesis and morphogenesis of limb synovial joints and articular cartilage. Matrix Biol. 2014;

    Google Scholar 

  189. Kan A, Ikeda T, Fukai A, Nakagawa T, Nakamura K, Chung UI, et al. SOX11 contributes to the regulation of GDF5 in joint maintenance. BMC Dev Biol. 2013;13:4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  190. Gao Y, Lan Y, Liu H, Jiang R. The zinc finger transcription factors Osr1 and Osr2 control synovial joint formation. Dev Biol. 2011;352(1):83–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  191. Dalgleish AE. Development of the limbs of the mouse: PhD Thesis, Stanford University; Stanford, CA. 1964.

    Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  193. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  194. 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.

    Article  CAS  PubMed  Google Scholar 

  195. 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.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  203. Sefton EM, Kardon G. Connecting muscle development, birth defects, and evolution: an essential role for muscle connective tissue. Curr Top Dev Biol. 2019;132:137–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  206. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  207. 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.

    Article  CAS  PubMed  Google Scholar 

  208. 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.

    Article  CAS  PubMed  Google Scholar 

  209. Dietrich S, Abou-Rebyeh F, Brohmann H, Bladt F, Sonnenberg-Riethmacher E, Yamaai T, et al. The role of SF/HGF and c-Met in the development of skeletal muscle. Development. 1999;126(8):1621–9.

    Article  CAS  PubMed  Google Scholar 

  210. 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.

    Article  CAS  PubMed  Google Scholar 

  211. 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.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  213. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  216. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  218. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  Google Scholar 

  220. 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.

    Article  CAS  PubMed  Google Scholar 

  221. 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 

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

    CAS  PubMed  Google Scholar 

  223. 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.

    Article  CAS  PubMed  Google Scholar 

  224. 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 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  227. 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.

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  229. 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.

    Article  PubMed  Google Scholar 

  230. Tonkin MA, Oberg KC. Congenital hand I - embryology, classification, and principles. In: Chang J, Neligan PC, editors. Plastic surgery, Hand and upper extremity, vol. 6. 3rd ed. Philadelphia: Elsevier; 2012. p. 526–47.

    Google Scholar 

  231. Saint-Hilaire IG. Propositions sur la monstruosit’e. Paris: Imp. Didot le Jeune; 1829.

    Google Scholar 

  232. 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 

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

    Google Scholar 

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

    Article  Google Scholar 

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

    Google Scholar 

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

    Google Scholar 

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

    Google Scholar 

  238. Kelikian H. Classifications. In: Kelikian H, editor. Congenital deformities of the hand and forearm. Philadelphia: WB Saunders; 1974. p. 51–88.

    Google Scholar 

  239. 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 

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

    Article  CAS  PubMed  Google Scholar 

  241. Ogino T. Congenital hand committee of the JSSH: modified IFSSH classification. J Japan Soc Surg Hand. 2000;17:353–65.

    Google Scholar 

  242. 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.

    Article  PubMed  Google Scholar 

  243. Tonkin MA, Tolerton SK, Quick TJ, Harvey I, Lawson RD, Smith NC, et al. Classification of congenital anomalies of the hand and upper limb: development and assessment of a new system. J Hand Surg Am. 2013;38(9):1845–53.

    Article  PubMed  Google Scholar 

  244. Ezaki M, Baek GH, Horii E, Hovius SE. IFSSH scientific committee on congenital conditions: classification of congenital hand and upper limb anomalies. IFSSH Ezine. 2014;4(2):14–6.

    Google Scholar 

  245. Goldfarb CA, Wall LB, Ezaki M, Oberg KC. Oberg-Manske-Tonkin (OMT) Classification of Congenital Upper Extremities: Update for 2020. J Hand Surg Am. 2020;45(6):542–7.

    Google Scholar 

  246. 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 Am. 2014;39(2):237–48.

    Article  PubMed  Google Scholar 

  247. Goldfarb CA, Wall LB, Bohn DC, Moen P, Van Heest AE: Epidemiology of congenital upper limb anomalies in a midwest United States population: an assessment using the Oberg, Manske, and Tonkin classification. J Hand Surg Am 2015, 40(1):127–32.e121–2.

    Google Scholar 

  248. Kantaputra PN, Carlson BM. Genetic regulatory pathways of split-hand/foot malformation. Clin Genet. 2019;95(1):132–9.

    Article  CAS  PubMed  Google Scholar 

  249. Sowinska-Seidler A, Socha M, Jamsheer A. Split-hand/foot malformation – molecular cause and implications in genetic counseling. J Appl Genet. 2014;55(1):105–15.

    Article  PubMed  Google Scholar 

  250. Itzkovitz B, Jiralerspong S, Nimmo G, Loscalzo M, Horovitz DD, Snowden A, et al. Functional characterization of novel mutations in GNPAT and AGPS, causing rhizomelic chondrodysplasia punctata (RCDP) types 2 and 3. Hum Mutat. 2012;33(1):189–97.

    Article  CAS  PubMed  Google Scholar 

  251. Morgan NV, Brueton LA, Cox P, Greally MT, Tolmie J, Pasha S, et al. Mutations in the embryonal subunit of the acetylcholine receptor (CHRNG) cause lethal and Escobar variants of multiple pterygium syndrome. Am J Hum Genet. 2006;79(2):390–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

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

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Ball, K.F., Tonkin, M.A., Oberg, K.C. (2021). Embryology and Classification of Congenital Upper Limb Anomalies. In: Laub Jr., D.R. (eds) Congenital Anomalies of the Upper Extremity. Springer, Cham. https://doi.org/10.1007/978-3-030-64159-7_1

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