The establishment of a receptive uterine environment is critical for embryonic survival and implantation. One gene that is expressed in the uterus during the peri-implantation period in mice and is required for female fertility is the homeobox gene Hoxa-10. Here we characterize the peri-implantation defects in Hoxa-10 mutant females and investigate functions of Hoxa-10 in the uterine anlage during morphogenesis and in the adult uterus during pregnancy. Examination of pregnancy in Hoxa-10 mutant females has revealed failure of implantation as well as resorption of embryos in the early postimplantation period. Morphologic analysis of the mutant uterus has demonstrated homeotic transformation of the proximal 25% into oviduct. Histology and molecular markers confirm this anterior transformation. Furthermore, in situ hybridization shows that this region coincides with the anterior limit of embryonic Hoxa-10 expression in the urogenital ducts and a parallel transformation is observed in Hoxa-10 mutant males at the junction of the epididymis and ductus deferens. Female fertility could be compromised by either the homeotic transformation or the absence of Hoxa-10 function in the adult during pregnancy. To distinguish between these two potential mechanisms of infertility, wildtype blastocysts were transferred into mutant uteri distal to the transformed region on day 2.5 of pseudopregnancy. This procedure did not rescue the phenotype, suggesting that adult uterine expression of Hoxa-10 is required during pregnancy. Moreover, when implantation was experimentally delayed, homozygous uteri were able to support survival of blastocysts comparable to wild-type controls, indicating that the requirement for Hoxa-10 is intrinsic to implantation. While expression of LIF and HB-EGF appears unaffected in the mutant uteri, a decrease is observed in the intensity and number of blue dye reactions, an indicator of increased vascular permeability in response to implantation. In addition, mutant uteri exhibited decreased decidualization in response to artificial stimuli. These results show that Hoxa-10 is required during morphogenesis for proper patterning of the reproductive tract and in the adult uterus for peri-implantation events.

Abrahamson
P. A.
,
Zorn
T. M. T.
(
1993
)
Implantation and decidualization in rodents.
J. Exp. Zool
266
,
603
628
Benson
G. V.
,
Nguyen
E. T.-H.
,
Maas
R. L.
(
1995
)
The expression pattern of the murine hoxa-10 gene and the sequence recognition of its homeodomain reveal specific properties of Abdominal B -like genes.
Mol. Cell Biol
15
,
1591
1601
Chapman
D. A.
,
Killian
G. J.
(
1984
)
Glycosidase activities in principal cells, basal cells, fibroblasts, and spermatozoa isolated from the rat epididymis.
Biol. Reprod
31
,
627
636
Cunha
G. R.
(
1976
)
Alterations in the developmental properties of stroma during the development of the urogenital ridge into ductus deferens and uterus in embryonic and neonatal mice.
J. Exp. Zool
197
,
375
388
Cunha
G. R.
(
1976
)
Stromal induction and specification of morphogenesis and cytodifferentiation of the epithelial of the Mullerian ducts and urogenital sinus during development of the uterus and vagina in mice.
J. Exp. Zool
196
,
361
370
Cunha
G. R.
,
Young
P.
,
Brody
J. R.
(
1989
)
Role of epithelium in the development of myometrial smooth muscle cells.
Biol. Reprod
40
,
861
871
Das
S. K.
,
Chakraborty
I.
,
Paria
B. C.
,
Wang
X.-N.
,
Plowman
G.
,
Dey
S. K.
(
1995
)
Amphiregulin is an implantation-specific and progesterone-regulated gene in the mouse uterus.
Mol. Endocrinol
9
,
691
705
Das
S. K.
,
Wang
X.-N.
,
Bibhash
C. P.
,
Damm
D.
,
Abraham
J. A.
,
Klagsbrun
M.
,
Andrews
G. K.
,
Dey
S. K.
(
1994
)
Heparin-binding EGF-like growth factor gene is induced in the mouse uterus temporally by the blastocyst solely at the site of its apposition: a possible ligand for interaction with blastocyst EGF-receptor in implantation.
Development
120
,
1071
1083
Dickmann
Z.
,
Noyes
R. W.
(
1960
)
The fate of ova transferred into the uterus of the rat.
J. Reprod. Fert
1
,
197
212
Dolle
P.
,
Izpisúa-Belmonte
J.-C.
,
Brown
J. M.
,
Tickle
C.
,
Duboule
D.
(
1991
)
Hox-4 genes and the morphogenesis of mammalian genitalia.
Genes Dev
5
,
1767
1776
Duboule
D.
(
1991
)
Patterning in the vertebrate limb.
Curr. Opin. Genet. Dev.,
1
,
211
216
Hafez
E. S.
,
Sugawara
S.
(
1978
)
Maternal effects on some biochemical characteristics of the blastocyst in the domestic rabbit.
J. Morph.,
130
,
353
365
Haney
A. F.
,
Newbold
R. R.
,
Fetter
B. F.
,
McLachlan
J. A.
(
1986
)
Paraovarian cysts associated with prenatal diethylstilbesterol exposure.
Am. J. Phys.,
124
,
405
411
Hetherington
C. M.
(
1968
)
The development of deciduomata by two non-traumatic methods in the mouse.
J. Reprod. Fert
17
,
391
393
Hsieh-Li
H. M.
,
Witte
D. P.
,
Weinstein
M.
,
Branford
W.
,
Li
H.
,
Small
K.
,
Potter
S. S.
(
1995
)
Hoxa11 structure, extensive antisense transcription, and function in male and female fertility.
Development
121
,
1373
385
Huet
Y. M.
,
Dey
S. K.
(
1987
)
Role of early and late oestrogenic effects on implantation in the mouse.
J. Reprod. Fert
81
,
453
458
Huet-Hudson
Y. M.
,
Andrews
G. K.
,
Dey
S. K.
(
1989
)
Cell type-specific localization of c-Myc protein in the mouse uterus: modulation by steroid hormones and analysis of the periimplantation period.
Endocrinology
125
,
1683
1690
Izpisúa-Belmonte
J. C.
,
De Robertis
E. M.
,
Storey
K. G.
,
Stern
C. D.
(
1993
)
The homeobox gene goosecoid and the origin of organizer cells in the early chick blastoderm.
Cell
74
,
645
659
Kessel
M.
,
Gruss
P.
(
1991
)
Homeotic transformations of murine vertebrae and concomitant alteration of Hox codes induced by retinoic acid.
Cell
67
,
89
104
Kirby
D. R. S.
(
1962
)
The influence of the uterine environment on the development of mouse eggs.
J. Embryol. Exp. Morph
10
,
496
506
Krumlauf
R.
(
1994
)
Hox genes in vertebrate development.
Cell
78
,
191
201
Morgenbesser
S. D.
,
Schreiber-Agus
N.
,
Bidder
M.
,
Mahon
K. A.
,
Overbeek
P. A.
,
Horner
J.
,
DePinho
R. A.
(
1995
)
Contrasting rolesfor c-Myc and L-Myc in the regulation of cellular growth and differentiation in vivo.
EMBO J
14
,
743
756
Papaioannou
V. E.
,
Gardner
R. L.
(
1992
)
Effects of diapause on lethal yellow (Ay/Ay) mouse embryos.
J. Exp. Zool
263
,
309
315
Paria
B. C.
,
Huet-Hudson
Y. M.
,
Dey
S. K.
(
1993
)
Blastocyst's state of activity determines the window of implantation.
Proc. Natl. Acad. Sci. USA
90
,
10159
10162
Pavlova
A.
,
Boutin
E.
,
Cunha
G.
,
Sassoon
D.
(
1994
).
Msx1 (Hox-7.1) in the adult mouse uterus: cellular interactions underlying regulation of expression.
Development
120
,
335
346
Redline
R. W.
,
Williams
A. J.
,
Patterson
P.
,
Collins
T.
(
1992
)
Human HOX4E: a gene strongly expressed in the adult male and female urogenital tracts.
Genomics,
13
,
425
430
Rijli
F. M.
,
Matyas
R.
,
Pellegrini
M.
,
Dierich
A.
,
Gruss
P.
,
Dolle
P.
,
Chambon
P.
(
1995
)
Cryptorchidism and homeotic transformations of spinal nerves and vertebrae in Hoxa-10 mutant mice.
Proc. Natl. Acad. Sci. USA
92
,
8185
8189
Sanes
J. R.
,
Rubenstein
J. L.
,
Nicolas
J. F.
(
1986
)
Use of a recombinant retrovirus to study post-implantation cell lineage in mouse embryos.
EMBO J
5
,
3133
3142
Satokata
I.
,
Benson
G. V.
,
Maas
R. L.
(
1995
)
Sexually dimorphic sterility phenotypes in Hoxa10-deficient mice.
Nature
374
,
460
463
Shima
H.
,
Tsuji
M.
,
Elfman
F.
,
Cunha
G. R.
(
1995
)
Development ofmale urogenital epithelia elicited by soluble mesenchymal factors.
J. Andrology
16
,
233
241
Simon
H. G.
,
Tabin
C. J.
(
1993
).
Analysis of Hox-4.5 and Hox-3.6 expression during newt limb regeneration: differential regulation of paralogous Hox genes suggest different roles for members of different Hox clusters.
Development
117
,
1397
1407
Stahl
J.
,
Gearing
D. P.
,
Willson
T. A.
,
Brown
M. A.
,
King
J. A.
,
Gough
N. M.
(
1990
)
Structural organization of the genes for murine and human leukemia inhibitory factor: Evolutionary conservation of coding and non-coding regions.
J. Biol. Chem
265
,
8833
8841
Stewart
C.
(
1994
)
Leukaemia inhibitory factor and the regulation of the pre-implantation development of the mammalian embryo.
Molecular Reprod. Dev
39
,
233
238
Stewart
C. L.
,
Kaspar
P.
,
Brunet
L. J.
,
Bhatt
H.
,
Gadi
I.
,
Kontgen
F.
,
Abbondanzo
S. J.
(
1992
)
Blastocyst implantation depends on maternal expression of leukaemia inhibitory factor.
Nature
359
,
76
79
Vogels
R.
,
DeGraaff
W.
,
Deschamps
J.
(
1990
).
Expression of the murine homeobox-containing gene Hox-2.3 suggests multiple time-dependent and tissue-specific roles during development.
Development
110
,
1159
1168
Ware
C. B.
,
Horowitz
M. C.
,
Renshaw
B. R.
,
Hunt
J. S.
,
Liggitt
D.
,
Koblar
S. A.
,
Gliniak
B. C.
,
McKenna
H. J.
,
Papayannopoulou
T.
,
Thoma
B.
,
Cheng
L.
,
Donovan
P. J.
,
Peschon
J.
,
Bartlett
P. F.
,
Willis
C. R.
,
Wright
B. D.
,
Carpenter
M. K.
,
Davison
B. L.
,
Gearing
D. P.
(
1995
)
Targeted disruption of the low affinity leukemia inhibitory factor receptor causes placental, skeletal, neural and metabolic defects and results in perinatal death.
Development
121
,
1283
1299
Yoshinaga
K.
,
Adams
C. E.
(
1966
)
Delayed implantation in the spayed, progesterone treated adult mouse.
J. Reprod. Fert
12
,
593
595
This content is only available via PDF.