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Handchir Mikrochir Plast Chir 2004; 36(2/03): 98-107
DOI: 10.1055/s-2004-817871
Original Article

Georg Thieme Verlag KG Stuttgart · New York

Embryology of the Upper Limb: The Molecular Orchestration of Morphogenesis

Embryologie der oberen ExtremitätK. C. Oberg1 , 2 , 3 , L. F. Greer1 , 4 , T. Naruse1 , 5
  • 1Divisions of Human Anatomy, Department of Pathology and Human Anatomy, Loma Linda University, Loma Linda, California, USA
  • 2Pediatric Pathology, Department of Pathology and Human Anatomy, Loma Linda University, Loma Linda, California, USA
  • 3Division of Plastic and Reconstructive Surgery, Department of Surgery, Loma Linda University, Loma Linda, California, USA
  • 4Department of Natural Sciences, Loma Linda University, Loma Linda, California, USA
  • 5Department of Orthopedic Surgery, Yamagata University, Yamagata, Japan
Further Information

Publication History

Received: October 2, 2003

Accepted: October 2, 2003

Publication Date:
26 May 2004 (online)

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Zusammenfassung

Unser Wissen um die Gliedmaßenmorphogenese wurde durch das Sammeln und Auswerten von Daten über molekulare Interaktionen während der Gliedmaßenentwicklung erheblich erweitert. In diesem Kapitel werden die morphologischen Schlüsselereignisse beschrieben, die allgemeinen Kategorien der beteiligten Moleküle definiert und die bekannten Molekularkaskaden und spezifischen Wege, die die Gliedmaßenentwicklung begleiten, beschrieben. Darüber hinaus werden die Kaskaden identifiziert, die durch bekannte genetische Mutationen bei Gliedmaßenmalformationen unterbrochen werden.

Abstract

Accumulating data on the molecular interactions that occur during limb development have greatly enhanced our understanding of the process of limb morphogenesis. In this chapter, the key morphologic events are described, the broad categories of molecules involved are defined, the known molecular cascades and specific pathways that orchestrate limb development are reviewed. In addition, cascades disrupted by known genetic mutations associated with limb malformations are identified.

Schlüsselwörter

Embryologie - obere Extremität - Handfehlbildungen - HOX-Gene

Key words

Review - signal transduction - transcription factors - HOX genes - WNT - FGF - BMP - SHH - limb development - patterning - limb anomalies

References

  • 1 Ahn K, Mishina Y, Hanks M C, Behringer R R, Crenshaw III E B. BMPR-IA signaling is required for the formation of the apical ectodermal ridge and dorsal-ventral patterning of the limb.  Development. 2001;  128 4449-4461
    PubMedSearch in Google Scholar
  • 2 Asahara H, Dutta S, Kao H Y, Evans R M, Montminy M. Pbx-Hox heterodimers recruit coactivator-corepressor complexes in an isoform-specific manner.  Mol Cell Biol. 1999;  19 8219-8225
    PubMedSearch in Google Scholar
  • 3 Barolo S, Posakony J W. Three habits of highly effective signaling pathways: principles of transcriptional control by developmental cell signaling.  Genes Dev. 2002;  16 1167-1181
    CrossrefPubMedSearch in Google Scholar
  • 4 Barrow J R, Thomas K R, Boussadia-Zahui O, Moore R, Kemler R, Capecchi M R, McMahon A P. Ectodermal Wnt3/beta-catenin signaling is required for the establishment and maintenance of the apical ectodermal ridge.  Genes Dev. 2002;  17 394-409
    PubMedSearch in Google Scholar
  • 5 Brandau O, Meindl A, Fassler R, Aszodi A. A novel gene, tendin, is strongly expressed in tendons and ligaments and shows high homology with chondromodulin-I.  Dev Dyn. 2001;  221 72-80
    CrossrefPubMedSearch in Google Scholar
  • 6 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 59-68
    CrossrefPubMedSearch in Google Scholar
  • 7 Burke A C, Nelson C E, Morgan B A, Tabin C. Hox genes and the evolution of vertebrate axial morphology.  Development. 1995;  121 333-346
    PubMedSearch in Google Scholar
  • 8 Bushdid P B, Chen C L, Brantley D M, Yull F, Raghow R, Kerr L D, Barnett J V. NF-kappaB mediates FGF signal regulation of msx-1 expression.  Dev Biol. 2001;  237 107-115
    CrossrefPubMedSearch in Google Scholar
  • 9 Chang C P, Brocchieri L, Shen W F, Largman C, Cleary M L. Pbx modulation of Hox homeodomain amino-terminal arms establishes different DNA-binding specificities across the Hox locus.  Mol Cell Biol. 1996;  16 1734-1745
    PubMedSearch in Google Scholar
  • 10 Charité J, de Graaff W, Shen S, Deschamps J. Ectopic expression of hoxb-8 causes duplication of the ZPA in the forelimb and homeotic transformation of axial structures.  Cell. 1994;  78 589-601
    CrossrefPubMedSearch in Google Scholar
  • 11 Charité J, McFadden D G, Olson E N. The bHLH transcription factor dHAND controls Sonic hedgehog expression and establishment of the zone of polarizing activity during limb development.  Development. 2000;  127 2461-2470
    PubMedSearch in Google Scholar
  • 12 Chen H, Lun Y, Ovchinnikov D, Kokubo H, Oberg K C, Pepicelli C V, Gan L, Lee B, Johnson R L. Limb and kidney defects in Lmx1b mutant mice suggest an involvement of LMX1 B in human nail patella syndrome.  Nat Genet. 1998;  19 51-55
    PubMedSearch in Google Scholar
  • 13 Cygan J A, Johnson R L, McMahon A P. Novel regulatory interactions revealed by studies of murine limb pattern in Wnt-7a and En-1 mutants.  Development. 1997;  124 5021-5032
    PubMedSearch in Google Scholar
  • 14 Dahn R D, Fallon J F. Interdigital regulation of digit identity and homeotic transformation by modulated BMP signaling.  Science. 2000;  289 438-441
    CrossrefPubMedSearch in Google Scholar
  • 15 Dolle P, Ruberte E, Kastner P, Petkovich M, Stoner C M, Gudas L J, Chambon P. Differential expression of genes encoding a, b and g retinoic acid receptors and CRABP in the developing limbs of the mouse.  Nature. 1989;  342 702-704
    CrossrefPubMedSearch in Google Scholar
  • 16 Duboule D. Vertebrate hox gene regulation: clustering and/or colinearity?.  Curr Opin Genet Dev. 1998;  8 514-518
    CrossrefPubMedSearch in Google Scholar
  • 17 Dudley A T, Ros M A, Tabin C J. A re-examination of proximodistal patterning during vertebrate limb development.  Nature. 2002;  418 539-544
    CrossrefPubMedSearch in Google Scholar
  • 18 Farrell E R, Munsterberg A E. csal1 is controlled by a combination of FGF and Wnt signals in developing limb buds.  Dev Biol. 2000;  225 447-458
    CrossrefPubMedSearch in Google Scholar
  • 19 Fernandez-Teran M, Piedra M E, Kathiriya I S, Srivastava D, Rodriguez-Rey J C, Ros M A. Role of dHAND in the anterior-posterior polarization of the limb bud: implications for the Sonic hedgehog pathway.  Development. 2000;  127 2133-2142
    PubMedSearch in Google Scholar
  • 20 Gerhart J. 1998 Warkany lecture: Signaling pathways in development.  Teratology. 1999;  60 226-239
    CrossrefPubMedSearch in Google Scholar
  • 21 Gibson-Brown J J, Agulnik S I, Silver L M, Niswander L, Papaioannou V E. Involvement of T-box genes Tbx2-Tbx5 in vertebrate limb specification and development.  Development. 1998;  125 2499-2509
    PubMedSearch in Google Scholar
  • 22 Grieshammer U, Minowada G, Pisenti J M, Abbott U K, Martin G R. The chick limbless mutation causes abnormalities in limb bud dorsal-ventral patterning: implications for the mechanism of apical ridge formation.  Development. 1996;  122 3851-3861
    PubMedSearch in Google Scholar
  • 23 Grotewold L, Theil T, Ruther U. Expression pattern of Dkk-1 during mouse limb development.  Mech Dev. 1999;  89 151-153
    CrossrefPubMedSearch in Google Scholar
  • 24 Halder G, Callaerts P, Gehring W J. Induction of ectopic eyes by targeted expression of the eyeless gene in Drosophila.  Science. 1995;  267 1788-1792
    PubMedSearch in Google Scholar
  • 25 Helms J, Thaller C, Eichele G. Relationship between retinoic acid and sonic hedgehog, two polarizing signals in the chick wing bud.  Development. 1994;  120 3267-3274
    PubMedSearch in Google Scholar
  • 26 Izpisua-Belmonte J C, Tickle C, Dolle P, Wolpert L, Duboule D. Expression of the homeobox Hox-4 genes and the specification of position in chick wing development.  Nature. 1991;  350 585-589
    CrossrefPubMedSearch in Google Scholar
  • 27 Johnson R L, Tabin C J. Molecular models for vertebrate limb development.  Cell. 1997;  90 979-990
    CrossrefPubMedSearch in Google Scholar
  • 28 Kawakami Y, Wada N, Nishimatsu S, Nohno T. Involvement of frizzled-10 in Wnt-7a signaling during chick limb development.  Dev Growth Differ. 2000;  42 561-569
    CrossrefPubMedSearch in Google Scholar
  • 29 Khan P, Linkhart B, Simon H. Different regulation of T-Box genes Tbx4 and Tbx5 during limb development and limb regeneration.  Dev Biol. 2002;  250 383
    CrossrefPubMedSearch in Google Scholar
  • 30 Linscheid R L. Evolution of the Human Hand. Scheker LR, Gupta A, Kay SPJ The Growing Hand: Diagnosis and Management of Conditions in the Pediatric Upper Extremity. London, UK; Mosby-Wolfe 2000: 1-4
    Search in Google Scholar
  • 31 Litingtung Y, Dahn R D, Li Y, Fallon J F, Chiang C. Shh and Gli3 are dispensable for limb skeleton formation but regulate digit number and identity.  Nature. 2002;  418 979-983
    CrossrefPubMedSearch in Google Scholar
  • 32 Lu H C, Revelli J P, Goering L, Thaller C, Eichele G. Retinoid signaling is required for the establishment of a ZPA and for the expression of Hoxb-8, a mediator of ZPA formation.  Development. 1997;  124 1643-1651
    PubMedSearch in Google Scholar
  • 33 Mann R S, Chan S-K. Extra specificity from extradenticle:the partnership between HOX and PBX/EXD homeodomain proteins.  TIG. 1996;  12 258-262
    PubMedSearch in Google Scholar
  • 34 Martin G R. The roles of FGFs in the early development of vertebrate limbs.  Genes Dev. 1998;  12 1571-1586
    PubMedSearch in Google Scholar
  • 35 Mills A A, Zheng B, Wang X J, Vogel H, Roop D R, Bradley A. p63 is a p53 homologue required for limb and epidermal morphogenesis.  Nature. 1999;  398 708-713
    CrossrefPubMedSearch in Google Scholar
  • 36 Ng J K, Kawakami Y, Buscher D, Raya A, Itoh T, Koth C M, Esteban C R, Rodriguez-Leon J, Garrity D M, Fishman M C, Izpisua-Belmonte J C. The limb identity gene Tbx5 promotes limb initiation by interacting with Wnt2b and Fgf10.  Development. 2002;  129 5161-5170
    PubMedSearch in Google Scholar
  • 37 Niederreither K, Vermot J, Schuhbaur B, Chambon P, Dolle P. Embryonic retinoic acid synthesis is required for forelimb growth and anteroposterior patterning in the mouse.  Development. 2002;  129 3563-3574
    PubMedSearch in Google Scholar
  • 38 O'Rourke M P, Soo K, Behringer R R, Hui C C, Tam P P. Twist plays an essential role in FGF and SHH signal transduction during mouse limb development.  Dev Biol. 2002;  248 143-156
    CrossrefPubMedSearch in Google Scholar
  • 39 Oberg K C, Eichele G. Hox gene expression and regulation in the presumptive wing region of the chick lateral plate mesoderm.  Dev Biol. 1999;  210 228-(Abstract)
    PubMedSearch in Google Scholar
  • 40 Ohuchi H, Nakagawa T, Itoh N, Noji S. FGF10 can induce Fgf8 expression concomitantly with En1 and R-fng expression in chick limb ectoderm, independent of its dorsoventral specification.  Dev Growth Differ. 1999;  41 665-673
    CrossrefPubMedSearch in Google Scholar
  • 41 Ohuchi H, Nakagawa T, Yamamoto A, Araga A, Ohata T, Ishimaru Y, Yoshioka H, Kuwana T, Nohno T, Yamasaki M, Itoh N, Noji S. 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 2235-2244
    PubMedSearch in Google Scholar
  • 42 Oliver G, Wehr R, Jenkins N A, Copeland N G, Cheyette B N, Hartenstein V, Zipursky S L, Gruss P. Homeobox genes and connective tissue patterning.  Development. 1995;  121 693-705
    PubMedSearch in Google Scholar
  • 43 Pagan S M, Ros M A, Tabin C, Fallon J F. Surgical removal of limb bud. Sonic hedgehog results in posterior skeletal defects.  Dev Biol. 1996;  180 35-40
    CrossrefPubMedSearch in Google Scholar
  • 44 Parr B A, McMahon A P. Dorsalizing signal Wnt-7a required for normal polarity of D-V and A-P axes of mouse limb.  Nature. 1995;  374 350-353
    CrossrefPubMedSearch in Google Scholar
  • 45 Peltenburg L T, Murre C. Specific residues in the Pbx homeodomain differentially modulate the DNA-binding activity of Hox and engrailed proteins.  Development. 1997;  124 1089-1098
    PubMedSearch in Google Scholar
  • 46 Peterson C, Martin G. Genetic analysis of fgf gene function in the limb.  Dev Biol. 2002;  247 LB35-(Abstract)
    PubMedSearch in Google Scholar
  • 47 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 4463-4474
    PubMedSearch in Google Scholar
  • 48 Pizette S, Niswander L. BMPs negatively regulate structure and function of the limb apical ectodermal ridge.  Development. 1999;  126 883-894
    PubMedSearch in Google Scholar
  • 49 Riddle R D, Ensini M, Nelson C, Tsuchida T, Jessell T M, Tabin C. Induction of the LIM homeobox gene Lmx1 by WNT7a establishes dorsoventral pattern in the vertebrate limb.  Cell. 1995;  83 631-640
    CrossrefPubMedSearch in Google Scholar
  • 50 Riddle R D, Johnson R L, Laufer E, Tabin C. Sonic hedgehog mediates the polarizing activity of the ZPA.  Cell. 1993;  75 1401-1416
    CrossrefPubMedSearch in Google Scholar
  • 51 Rodriguez-Esteban C, Schwabe J WR, De La Pena J, Foys B, Eshelman B, Izpisua-Belmonte J C. Radical fringe positions the apical ectodermal ridge at the dorsoventral boundary of the vertebrate limb.  Nature. 1997;  386 360-365
    CrossrefPubMedSearch in Google Scholar
  • 52 Rodriguez-Esteban C, Tsukui T, Yonei S, Magallon J, Tamura K, Izpisua Belmonte J C. The T-box genes Tbx4 and Tbx5 regulate limb outgrowth and identity.  Nature. 1999;  398 814-818
    CrossrefPubMedSearch in Google Scholar
  • 53 Ros M A, Lopez-Martinez A, Simandl B K, Rodriguez C, Izpisua Belmonte J C, Dahn R, Fallon J F. The limb field mesoderm determines initial limb bud anteroposterior asymmetry and budding independent of sonic hedgehog or apical ectodermal gene expressions.  Development. 1996;  122 2319-2330
    PubMedSearch in Google Scholar
  • 54 Salas-Vidal E, Valencia C, Covarrubias L. Differential tissue growth and patterns of cell death in mouse limb autopod morphogenesis.  Dev Dyn. 2001;  220 295-306
    CrossrefPubMedSearch in Google Scholar
  • 55 Schweitzer R, Chyung J H, Murtaugh L C, Brent A E, Rosen V, Olson E N, Lassar A, Tabin C J. Analysis of the tendon cell fate using Scleraxis, a specific marker for tendons and ligaments.  Development. 2001;  128 3855-3866
    PubMedSearch in Google Scholar
  • 56 Smith S M, Kirstein I J, Wang Z S, Fallon J F, Kelley J, Bradshaw-Rouse J. Differential expression of retinoic acid receptor-beta isoforms during chick limb ontogeny.  Dev Dyn. 1995;  202 54-66
    PubMedSearch in Google Scholar
  • 57 Sun X, Lewandoski M, Meyers E N, Liu Y H, Maxson Jr R E, Martin G R. Conditional inactivation of Fgf4 reveals complexity of signalling during limb bud development.  Nat Genet. 2000;  25 83-86
    PubMedSearch in Google Scholar
  • 58 Taipale J, Cooper M K, Maiti T, Beachy P A. Patched acts catalytically to suppress the activity of Smoothened.  Nature. 2002;  418 892-897
    CrossrefPubMedSearch in Google Scholar
  • 59 Tavares A T, Tsukui T, Izpisua Belmonte J C. Evidence that members of the Cut/Cux/CDP family may be involved in AER positioning and polarizing activity during chick limb development.  Development. 2000;  127 5133-5144
    PubMedSearch in Google Scholar
  • 60 te Welscher P, Zuniga A, Kuijper S, Drenth T, Goedemans H J, Meijlink F, Zeller R. Progression of vertebrate limb development through SHH-mediated counteraction of GLI3.  Science. 2002;  298 827-830
    CrossrefPubMedSearch in Google Scholar
  • 61 Vogel A, Rodriguez C, Warnken W, Izpisua Belmonte J C. Dorsal cell fate specified by chick Lmx1 during vertebrate limb development.  Nature. 1995;  378 716-720
    CrossrefPubMedSearch in Google Scholar
  • 62 Wada N, Nohno T. Differential response of Shh expression between chick forelimb and hindlimb buds by FGF-4.  Dev Dyn. 2001;  221 402-411
    CrossrefPubMedSearch in Google Scholar
  • 63 Wang B, Fallon J F, Beachy P A. Hedgehog-regulated processing of Gli3 produces an anterior/posterior repressor gradient in the developing vertebrate limb.  Cell. 2000;  100 423-434
    CrossrefPubMedSearch in Google Scholar
  • 64 Xu P X, Cheng J, Epstein J A, Maas R L. Mouse Eya genes are expressed during limb tendon development and encode a transcriptional activation function.  Proc Natl Acad Sci USA. 1997;  94 11974-11979
    CrossrefPubMedSearch in Google Scholar
  • 65 Yokouchi Y, Sasaki H, Kuroiwa A. Homeobox gene expression correlated with the bifurcation process of limb cartilage development.  Nature. 1991;  353 443-445
    CrossrefPubMedSearch in Google Scholar

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

Division of Human Anatomy
Loma Linda University

24745 Stewart St.

Loma Linda, CA 92350

USA

Email: koberg@som.llu.edu