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
-
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
-
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
-
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
-
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
-
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
-
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
-
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
-
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
-
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
-
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
-
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
-
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
-
14
Dahn R D, Fallon J F.
Interdigital regulation of digit identity and homeotic transformation by modulated BMP signaling.
Science.
2000;
289
438-441
-
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
-
16
Duboule D.
Vertebrate hox gene regulation: clustering and/or colinearity?.
Curr Opin Genet Dev.
1998;
8
514-518
-
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
-
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
-
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
-
20
Gerhart J.
1998 Warkany lecture: Signaling pathways in development.
Teratology.
1999;
60
226-239
-
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
-
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
-
23
Grotewold L, Theil T, Ruther U.
Expression pattern of Dkk-1 during mouse limb development.
Mech Dev.
1999;
89
151-153
-
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
-
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
-
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
-
27
Johnson R L, Tabin C J.
Molecular models for vertebrate limb development.
Cell.
1997;
90
979-990
-
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
-
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
-
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
-
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
-
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
-
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
-
34
Martin G R.
The roles of FGFs in the early development of vertebrate limbs.
Genes Dev.
1998;
12
1571-1586
-
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
-
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
-
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
-
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
-
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)
-
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
-
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
-
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
-
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
-
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
-
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
-
46
Peterson C, Martin G.
Genetic analysis of fgf gene function in the limb.
Dev Biol.
2002;
247
LB35-(Abstract)
-
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
-
48
Pizette S, Niswander L.
BMPs negatively regulate structure and function of the limb apical ectodermal ridge.
Development.
1999;
126
883-894
-
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
-
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
-
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
-
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
-
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
-
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
-
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
-
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
-
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
-
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
-
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
-
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
-
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
-
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
-
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
-
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
-
65
Yokouchi Y, Sasaki H, Kuroiwa A.
Homeobox gene expression correlated with the bifurcation process of limb cartilage development.
Nature.
1991;
353
443-445
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
