Pax 1 is a member of the paired-box containing gene family. Expression has previously been observed in the developing sclerotomes and later in the anlagen of the intervertebral discs. Analysis of Pax 1-deficient undulated mice revealed an important role for this gene in the development of the axial skeleton, in which Pax 1 apparently functions as a mediator of notochordal signals during sclerotome differentiation. Here we demonstrate that Pax 1 is also transiently expressed in the developing limb buds. A comparative phenotypic analysis of different undulated alleles shows that this expression is of functional significance. In mice that are mutant for the Pax 1 gene severe developmental abnormalities are found in the pectoral girdle. These include fusions of skeletal elements which would normally remain separate, and failures in the differentiation of blastemas into cartilaginous structures. Although Pax 1 is also expressed in the developing hindlimb buds and Wolffian ridge, no malformations could be detected in the corresponding regions of Pax 1 mutant mice. These findings show that, in addition to its role in the developing vertebral column, Pax 1 has an important function in the development of parts of the appendicular skeleton.

REFERENCES

Balcuns
A.
,
Gasseling
M. T.
,
Saunders
J. W.
(
1970
)
Spatiotemporal distribution of a zone that controls antero-posterior polarity in the limb bud of the chick and other bird embryos.
Am Zool
10
,
323
–.
Balling
R.
,
Deutsch
U.
,
Gruss
P.
(
1988
)
undulated, a mutation affecting the development of the mouse skeleton has a point mutation in the paired box of Pax-1.
Cell
55
,
532
535
Balling
R.
,
Lau
C. F.
,
Dietrich
S.
,
Wallin
J.
,
Gruss
P.
(
1992
)
Development of the skeletal system.
Ciba Foundation Symposium
165
,
132
145
Beresford
B.
(
1983
)
Brachial muscles in the chick embryo. the fate of individual somites.
J. Embryol. Exp. Morph
77
,
99
116
Bopp
D.
,
Burri
M.
,
Baumgartner
S.
,
Frigerio
G.
,
Noll
M.
(
1986
)
Conservation of a large protein domain in the segmentation gene paired and in functionally related genes of Drosophila.
Cell
47
,
1033
1040
Brand-Saberi
B.
,
Ebensperger
C.
,
Wilting
J.
,
Balling
R.
,
Christ
B.
(
1993
)
The ventralizing effect of the notochord on somite differentiation in chick embryos.
Anat. Embryol
188
,
239
245
Chalepakis
G.
,
Fritsch
R.
,
Fickenscher
H.
,
Deutsch
U.
,
Goulding
M.
,
Gruss
P.
(
1991
)
The molecular basis of the undulated/Pax-1 mutation.
Cell
66
,
873
884
Chalepakis
G.
,
Stoykova
A.
,
Wijnholds
J.
,
Tremblay
P.
,
Gruss
P.
(
1993
)
Pax: gene regulators in the developing nervous system.
J. Neurobiol
24
,
1367
1384
Cheah
K. S. E.
,
Lau
E. T.
,
Au
P. K. C.
,
Tam
P. P. L.
(
1991
)
Expression of the mouse1(II) collagen gene is not restricted to cartilage during development.
Development
111
,
945
953
Chevallier
A.
(
1977
)
Origine des ceintures scapulaires et pelviennes chez l'embryon d'oiseau.
J. Embryol. Exp. Morphol
42
,
275
292
Czerny
T.
,
Schaffner
G.
,
Busslinger
M.
(
1993
)
DNA sequence recognition by Pax proteins: bipartite structure of the paired domain and its binding site.
Genes Dev
7
,
2048
2061
Deutsch
U.
,
Dressler
G. R.
,
Gruss
P.
(
1988
)
Pax-1, a member of a paired box homologous murine gene family, is expressed in segmented structures during development.
Cell
53
,
617
625
Dietrich
S.
,
Schubert
F. R.
,
Gruss
P.
(
1993
)
Altered Pax gene expression in murine notochord mutants: the notochord is required to initiate and maintain ventral identity in the somite.
Mech. Dev
44
,
189
207
Dolle
P.
,
Dierich
A.
,
LeMeur
M.
,
Schimmang
T.
,
Schuhbaur
B.
,
Chambon
P.
,
Duboule
D.
(
1993
)
Disruption of the Hoxd-13 gene induces localized heterochrony leading to mice with neotenic limbs.
Cell
75
,
431
441
Gruneberg
H.
(
1950
)
Genetical studies on the skeleton of the mouse. II. Undulated and its ‘modifiers’.
J. Genet
50
,
142
173
Gruneberg
H.
(
1954
)
Genetical studies on the skeleton of the mouse XII. The development of undulated.
J. Genet
52
,
441
455
Haack
H.
,
Gruss
P.
(
1993
)
The establishment of murine Hox-1 expression domains during patterning of the limb.
Dev. Biol
157
,
410
422
Hill
R.
,
van Heyningen
V.
(
1992
)
Mouse mutations and human disorders are paired.
Trends Genet
8
,
119
120
Jegalian
B. G.
,
Miller
R. W.
,
Wright
C. V. E.
,
Blum
M.
,
De Robertis
E.
(
1992
).
A Hox 3.3 -lacZ transgene expressed in developing limbs.
Mech. Dev
39
,
171
180
Koseki
H.
,
Wallin
J.
,
Wilting
J.
,
Mizutani
Y.
,
Kispert
A.
,
Ebensperger
C.
,
Herrmann
B. G.
,
Christ
B.
,
Balling
R.
(
1993
)
A role for Pax-1 as a mediator of notochordal signals during the dorsoventral specification of vertebrae.
Development
119
,
649
660
Maulbecker
C. C.
,
Gruss
P.
(
1993
)
The oncogenic potential of Pax genes.
EMBO J
12
,
2361
2367
Metsäranta
M.
,
Tomanm
D.
,
deCrombrugghe Vuorio
E.
(
1991
)
Mouse type II collagen gene.
J. Biol. Chem
266
,
16862
16869
Morgan
B. A.
,
Izpisua-Belmonte
J. C.
,
Duboule
D.
,
Tabin
C.
(
1992
).
Targeted misexpression of Hox 4.6 in the avian limb bud causes apparent homeotic transformation.
Nature
358
,
236
239
Morgan
B. A.
,
Tabin
C. J.
(
1993
)
The role of homeobox genes in limb development.
Curr. Opin. Genet. Dev
3
,
668
674
Niswander
L.
,
Martin
G.
(
1993
)
FGF-4 and BMP-2 have opposite effects on limb growth.
Nature
361
,
68
71
Noll
M.
(
1993
)
Evolution and role of Pax genes.
Curr. Opin. Genet. Dev
3
,
595
605
Oliver
G.
,
Wright
C. V. E.
,
Hardwicke
J.
,
De Robertis
E. M.
(
1988
)
A gradient of homeodomain protein in developing forelimbs of Xenopus and mouse embryos.
Cell
55
,
1017
1024
Oliver
G.
,
De Robertis
E. M.
,
Wolpert
L.
,
Tickle
C.
(
1990
)
Expression of a homeobox gene in the chick wing bud following application of retinoic acid and grafts of polarizing region tissue.
EMBO J
9
,
3093
3099
Riddle
R. D.
,
Johnson
R. L.
,
Laufer
E.
,
Tabin
C.
(
1993
)
Sonic hedgehog mediates the polarizing activity of the ZPA.
Cell
75
,
1401
1416
Saunders
J. W.
(
1948
)
The proximo-distal sequence of origin of the parts of the chick wing and the role of the ectoderm.
J. Exp. Zool
108
,
363
404
Searls
R. L.
,
Janners
M. Y.
(
1971
)
The initiation of limb bud outgrowth in the embryonic chick.
Dev. Biol
24
,
198
213
Sharpe
P. T.
,
Miller
J. R.
,
Evans
E. P.
,
Burtenshaw
M. D.
,
Gaunt
S.J.
(
1988
)
Isolation and expression of a new mouse homeobox gene.
Development
102
,
397
407
Stapleton
P.
,
Weith
A.
,
Urbánek
P.
,
Kozmik
Z.
,
Busslinger
M.
(
1993
)
Chromosomal localization of seven PAX genes and cloning of a novel family member, PAX-9.
Nature Genetics
3
,
292
298
Swalla
B. J.
,
Upholt
W. B.
,
Solursh
M.
(
1988
)
Analysis of type II collagen RNA localization in chick wing buds by in situ hybridization.
Dev. Biol
125
,
51
58
Tickle
C.
,
Alberts
B.
,
Wolpert
L.
,
Lee
J.
(
1982
)
Local application of retinoic acid to the limb bud mimics the action of the polarizing region.
Nature
296
,
564
566
Treisman
J.
,
Harris
E.
,
Desplan
C.
(
1991
)
The paired box encodes a second DNA-binding domain in the paired homeo domain protein.
Genes Dev
5
,
594
604
Wallace
M.
(
1985
)
An inherited agent of mutation with chromosome damage in wild mice.
J. Hered
76
,
271
278
Wallin
J.
,
Mizutani
Y.
,
Imai
K.
,
Miyashita
N.
,
Moriwaki
K.
,
Taniguchi
M.
,
Koseki
H.
,
Balling
R.
(
1993
)
A new Pax gene, Pax-9, maps to mouse chromosome 12.
Mammalian Genome
4
,
354
358
Wallin
J.
,
Wilting
J.
,
Koseki
H.
,
Fritsch
R.
,
Christ
B.
,
Balling
R.
(
1994
)
The role of Pax-1 in axial skeleton development.
Development
120
,
1109
1121
Walther
C.
,
Guenet
J.-L.
,
Simon
D.
,
Deutsch
U.
,
Jostes
B.
,
Goulding
M. D.
,
Plachov
D.
,
Balling
R.
,
Gruss
P.
(
1991
)
Pax: a murine multigene family of paired box-containing genes.
Genomics
11
,
424
434
Wanek
N.
,
Muneoka
K.
,
Holler-Dinsmore
G.
,
Burton
R.
,
Bryant
S.
(
1989
)
A staging system for mouse limb development.
J. Exp. Zool
249
,
41
49
Wanek
N.
,
Gardiner
D. M.
,
Muneoka
K.
,
Bryant
S. V.
(
1991
)
Conversion by retinoic acid of anterior cells into ZPA cells in the chick wing bud.
Nature
350
,
81
83
Wright
M. E.
(
1947
)
undulated: A new genetic factor in Mus musculus affecting the spine and tail.
Heredity
1
,
137
141
Yander
G.
,
Searls
R.
(
1980
)
An experimental analysis of shoulder and lateral body wall development in the chick embryo.
J. Exp. Zool
214
,
79
92
Yokouchi
Y.
,
Sasaki
H.
,
Kuroiwa
A.
(
1991
)
Homeobox gene expression correlated with the bifurcation process of limb cartilage development.
Nature
353
,
443
445
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