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First published online 3 March 2004
doi: 10.1242/dev.01038
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1 Department of Anatomy, University of California, San Francisco, CA 94143-0452,
USA
2 Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA
* Author for correspondence (e-mail: kurita{at}itsa.ucsf.edu)
Accepted 15 December 2003
Women exposed to diethylstilbestrol (DES) in utero develop abnormalities,
including cervicovaginal adenosis that can lead to cancer. We report that
transient disruption of developmental signals by DES permanently changes
expression of p63, thereby altering the developmental fate of Müllerian
duct epithelium. The cell fate of Müllerian epithelium to be columnar
(uterine) or squamous (cervicovaginal) is determined by mesenchymal induction
during the perinatal period. Cervicovaginal mesenchyme induced p63 in
Müllerian duct epithelium and subsequent squamous differentiation. In
p63–/– mice, cervicovaginal epithelium
differentiated into uterine epithelium. Thus, p63 is an identity switch for
Müllerian duct epithelium to be cervicovaginal versus uterine. P63 was
also essential for uterine squamous metaplasia induced by DES-exposure.
DES-exposure from postnatal day 1 to 5 inhibited induction of p63 in
cervicovaginal epithelium via epithelial ER
. The inhibitory effect of
DES was transient, and most cervicovaginal epithelial cells recovered
expression of p63 by 2 days after discontinuation of DES-treatment. However,
some cervicovaginal epithelial cells failed to express p63, remained columnar
and persisted into adulthood as adenosis.
Key words: Columnar-squamous transformation, Müllerian duct, Endocrine disruptor, Uterus, Estrogen receptor
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