Conditional deletion of h-catenin in the mesenchyme of the developing
mouse uterus results in a switch to adipogenesis in the myometrium
Nelson A. Arangoa, Paul P. Szoteka, Thomas F. Manganaroa, Esther Olivab,
Patricia K. Donahoea, Jose Teixeiraa,*
aPediatric Surgical Research Laboratories/CPZN6202, Massachusetts General Hospital and Harvard Medical School, 185 Cambridge St., Boston, MA 02114, USA
bDepartment of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
Received for publication 5 May 2005, revised 28 September 2005, accepted 30 September 2005
Available online 27 October 2005
Precise cell fate decisions during differentiation of uterine tissues from the embryonic Mu ¨llerian duct are critical for normal fertility. Wnt-7a, a
member of the Wnt family of secreted signaling molecules that can signal through a canonical h-catenin pathway, is necessary for the correct
differentiation of both anterior/posterior and radial axes of the uterus. In order to investigate the role of h-catenin directly in mouse uterine
development, we have generated mice that are deficient in h-catenin expression in the embryonic Mu ¨llerian duct. We have found that conditional
deletion of h-catenin in the Mu ¨llerian duct mesenchyme before postnatal differentiation of the uterine layers results in a phenotype that is distinct
from the phenotype observed by deletion of Wnt-7a. Shortly after birth, the uteri of the conditional mutants appear smaller and less organized. The
uteri of adult conditional h-catenin mutants are grossly deficient in smooth muscle of the myometrium, which has been replaced by adipose, a
phenotype resembling human lipoleiomyoma. We also show that the adipocytes in the uteri of mice conditionally deleted for h-catenin are derived
from Mu ¨llerian inhibiting substance type II receptor-expressing cells suggesting that they share a common origin with the uterine smooth muscle
cells. These results describe the first molecular evidence linking disruption of h-catenin expression in mesenchymal cells with a switch from
myogenesis to adipogenesis in vivo.
D 2005 Elsevier Inc. All rights reserved.
Keywords: Uterus; Myometrium; Mu ¨llerian duct; Mesenchyme; h-Catenin; Adipogenesis; Myogenesis
The embryonic Mu ¨llerian ducts are derived from the
invagination of coelomic epithelium in the bilateral urogenital
ridges during differentiation of the bipotential gonad. In male
embryos, expression of Mu ¨llerian Inhibiting Substance (MIS,
also known as antiMu ¨llerian hormone, AMH (Josso et al.,
1993)) by Sertoli cells in the differentiating testes causes
Mu ¨llerian duct regression. In female embryos, the absence of
MIS allows the Mu ¨llerian duct to differentiate into the internal
female reproductive tract structures: the cervix, uterus, and
oviducts or Fallopian tubes (Kurita et al., 2001). Despite the
relative importance of these tissues for reproduction and thus,
continuation of the species, little is known about the molecular
mechanisms that regulate their embryonal or postnatal phases of
differentiation. Mu ¨llerian duct agenesis has been described in
mice mutants lacking the homeodomain transcription factors
Pax2, Lim1, and Emx2 as well as in mice lacking Wnt4, a
member of the WNT gene family of secreted signaling
molecules (Kobayashi and Behringer, 2003). Another WNT
family member, Wnt7a, which is expressed in the luminal
epithelia of the relatively simple uterine tube, is necessary for
and radial axes of the epithelial and stromal layers. Wnt7a,
which along with the homeobox proteins Hoxa10, Hoxa11, and
Hoxa13, is also necessary for the morphogenesis of the cervix,
oviducts, and uterine corpus from the primitive uterine tube
(Kobayashi and Behringer, 2003). The canonical Wnt signaling
cascade utilizes the transcription cofactor, h-catenin, which
otherwise functions as a structural adaptor protein linking
and Nusse, 2004). Homozygous deletion of the h-catenin gene
is embryonically lethal at gastrulation (Haegel et al., 1995).
0012-1606/$ - see front matter D 2005 Elsevier Inc. All rights reserved.
* Corresponding author.
E-mail address: email@example.com (J. Teixeira).
Developmental Biology 288 (2005) 276 – 283
manuscript. These studies were supported through a coopera-
tive agreement U54 HD28138 as part of the Specialized
Cooperative Centers Program in Reproduction Research fro the
NICHD (JT) and by NICHD R01HD32112 (PKD). NAA is
supported by an NICHD NRSA grant, F32HD43539.
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