Ulnaless (Ul), an X-ray-induced dominant mutation in mice, severely disrupts development of forearms and forelegs. The mutation maps on chromosome 2, tightly linked to the HoxD complex, a cluster of regulatory genes required for proper morphogenesis. In particular, 5′-located (posterior) Hoxd genes are involved in limb development and combined mutations within these genes result in severe alterations in appendicular skeleton. We have used several engineered alleles of the HoxD complex to genetically assess the potential linkage between these two loci. We present evidence indicating that Ulnaless is allelic to Hoxd genes. Important modifications in the expression patterns of the posterior Hoxd-12 and Hoxd-13 genes at the Ul locus suggest that Ul is a regulatory mutation that interferes with a control mechanism shared by multiple genes to coordinate Hoxd function during limb morphogenesis.

Chan
D. C. A.
,
Wynshaw-Boris
A.
,
Leder
P.
(
1995
)
Formin isoforms are differentially expressed in the mouse embryo and are required for normal expression of fgf-4 and shh in the limb bud.
Development
121
,
3151
3161
Davis
A. P.
,
Capecchi
M. R.
(
1994
)
Axial homeosis and appendicular skeleton defects in mice with a targeted disruption of Hoxd-11.
Development
120
,
2187
2198
Davis
A. P.
,
Capecchi
M. R.
(
1996
)
A mutational analysis of the 5 HoxD genes: Dissection of genetic interactions during limb development in the mouse.
Development
122
,
1175
1185
Davis
A. P.
,
Witte
D. P.
,
Hsieh-Li
H. M.
,
Potter
S. S.
,
Capecchi
M. R.
(
1995
)
Absence of radius and ulna in mice lacking Hoxa-11 and Hoxd-11.
Nature
375
,
791
795
Davisson
M. T.
,
Cattanach
B. M.
(
1990
)
The mouse mutation Ulnaless on chromosome 2.
J. Hered
81
,
151
153
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
Dolle
P.
,
Duboule
D.
(
1989
)
Two gene members of the murine HOX-5 complex show regional and cell-type specific expression in developing limbs and gonads.
EMBO J
8
,
1507
15
Dolle
P.
,
Izpisúa-Belmonte
J.-C.
,
Tickle
C.
,
Brown
J.
,
Duboule
D.
(
1991
)
Hox-4 genes and the morphogenesis of mammalian genitalia.
Genes Dev
5
,
1767
1776
Dolle
P.
,
Izpisúa-Belmonte
J.-C.
,
Boncinelli
E.
,
Duboule
D.
(
1991
).
The Hox-4.8 gene is localized at the 5extremity of the Hox-4 complex and is expressed in the most posterior parts of the body during development.
Mech. Dev
36
,
3
13
Duboule
D.
(
1991
)
Patterning in the vertebrate limb.
Curr. Opin. Genet. Dev
1
,
211
6
Duboule
D.
,
Morata
G.
(
1994
)
Colinearity and functional hierarchy among genes of the homeotic complexes.
Trends Genet
10
,
358
364
Favier
B.
,
Le Meur
M.
,
Chambon
P.
,
Dolle
P.
(
1995
)
Axial skeleton homeosis and forelimb malformations in Hoxd-11 mutant mice.
Proc. Natl. Acad. Sci. USA
92
,
310
314
Featherstone
M. S.
,
Baron
A.
,
Gaunt
S. J.
,
Mattei
M. G.
,
Duboule
D.
(
1988
).
Hox-5.1 defines a homeobox-containing gene locus on mouse chromosome 2.
Proc. Natl. Acad. Sci. USA
85
,
4760
4764
Fromental-Ramain
C.
,
Warot
X.
,
Lakkaraju
S.
,
Favier
B.
,
Haack
H.
,
Birling
C.
,
Dierich
A.
,
Dolle
P.
,
Chambon
P.
(
1996
)
Specific and redundant functions of the paralogous Hoxa-9 and Hoxd-9 genes in forelimb and axial skeleton patterning.
Development
122
,
461
472
Fromental-Ramain
C.
,
Warot
X.
,
Messadecq
N.
,
Lemeur
M.
,
Dolle
P.
,
Chambon
P.
(
1996
)
Hoxa-13 and Hoxd-13 play a crucial role in the patterning of the limb autopod.
Development
122
,
2997
3011
Gerard
M.
,
Chen
J.-Y.
,
Gronemeyer
H.
,
Chambon
P.
,
Duboule
D.
,
Zákány
J.
(
1996
)
In vivo targeting of a regulatory element required forpositioning the Hoxd-11 and Hoxd-10 expression boundaries.
Genes Dev
18
,
2326
2334
Goff
D. J.
,
Tabin
C. J.
(
1997
)
Analysis of Hoxd-13 and Hoxd-11 misexpression in chicken limb buds reveals that Hox genes affect both bone condensation and growth.
Development
124
,
627
636
Haramis
A. G.
,
Brown
J. M.
,
Zeller
R.
(
1995
)
The limb deformity mutation disrupts the SHH/FGF-4 feedback loop and regulation of 5 HoxD genes during limb pattern formation.
Development
121
,
4237
4245
Izpisúa-Belmonte
J.-C.
,
Falkenstein
H.
,
Dolle
P.
,
Renucci
A.
,
Duboule
D.
(
1991
)
Murine genes related to the Drosophila AbdB homeotic genes are sequentially expressed during development of the posterior part of the body.
EMBO J
10
,
2279
2289
Kondo
T.
,
Dolle
P.
,
Zákány
J.
,
Duboule
D.
(
1996
)
Function of posterior HoxD genes in the morphogenesis of the anal sphincter.
Development
122
,
2651
2659
Kuhlman
J.
,
Niswander
L.
(
1997
)
Limb deformity proteins: role in mesodermal induction of the apical ectodermal ridge.
Development
124
,
133
139
Mortlock
D. P.
,
Innis
J. W.
(
1997
)
Mutation of HOXA13 in hand-foot-genital syndrome.
Nature Genet
15
,
179
180
Mortlock
D. P.
,
Post
L. C.
,
Innis
J. W.
(
1996
)
The molecular basis of hypodactyly (Hd): A deletion in Hoxa13 leads to arrest of digital arch formation.
Nature Genet
13
,
284
289
Muenke
M.
,
Schell
U.
(
1995
)
Fibroblast-growth-factor receptor mutations in human skeletal disorders.
Trends Genet
11
,
308
313
Muragaki
Y.
,
Mundlos
S.
,
Upton
J.
,
Olsen
B. R.
(
1996
)
Altered growth and branching patterns in synpolydactyly caused by mutations in HOXD13.
Science
272
,
548
551
Peichel
C. L.
,
Abbott
C. M.
,
Vogt
T. F.
(
1996
)
Genetic and physical mapping of the mouse Ulnaless locus.
Genetics
144
,
1757
1767
Peichel
C. L.
,
Prabhakaran
B.
,
Vogt
T. F.
(
1997
)
The mouse Ulnaless mutation deregulates posterior Hoxd gene colinearity and alters appendicular patterning.
Development
124
,
3481
3492
Small
K. M.
,
Potter
S. S.
(
1993
)
Homeotic transformation and limb defects in Hoxa-11 mutant mice.
Genes Dev
7
,
2318
2328
van der Hoeven
F.
,
Zákány
J.
,
Duboule
D.
(
1996
)
Gene transpositions in the HoxD complex reveal a hierarchy of regulatory controls.
Cell
85
,
1025
1035
Woychik
R. P.
,
Maas
R. L.
,
Zeller
R.
,
Vogt
T. F.
,
Leder
P.
(
1990
)
‘Formins’: Proteins deduced from the alternative transcripts of the limb deformity gene.
Nature
346
,
850
853
Yamaguchi
T. P.
,
Rossant
J.
(
1995
)
Fibroblast growth factors in mammalian development.
Cur. Opin. Gen. and Dev
5
,
485
491
Yokouchi
Y.
,
Nakazato
S.
,
Yamamoto
M.
,
Goto
Y.
,
Kameda
T.
,
Iba
H.
,
Kuroiwa
A.
(
1995
)
Misexpression of Hoxa-13 induces cartilage homeotic transformation and changes cell adhesiveness in chick limb buds.
Genes Dev
9
,
2509
2522
Zákány
J.
,
Duboule
D.
(
1996
)
Synpolydactyly in mice with a targeted deficiency in the HoxD complex.
Nature
384
,
69
71
This content is only available via PDF.