期刊
DEVELOPMENT
卷 131, 期 7, 页码 1639-1649出版社
COMPANY BIOLOGISTS LTD
DOI: 10.1242/dev.01038
关键词
columnar-squamous transformation; mullerian duct; endocrine disruptor; uterus; estrogen receptor alpha
资金
- NIA NIH HHS [AG 15500, AG 13784] Funding Source: Medline
- NIDDK NIH HHS [DK 47515, DK 52707] Funding Source: Medline
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 Mullerian duct epithelium. The cell fate of Mullerian epithelium to be columnar (uterine) or squamous (cervicovaginal) is determined by mesenchymal induction during the perinatal period. Cervicovaginal mesenchyme induced p63 in Mullerian duct epithelium and subsequent squamous differentiation. In p63(-/-) mice, cervicovaginal epithelium differentiated into uterine epithelium. Thus, p63 is an identity switch for Mullerian duct epithelium to be cervicovaginal versus uterine. P63 was also essential for uterine squamous metaplasia induced by DES-exposure. DES-exposure from postnatal day I to 5 inhibited induction of p63 in cervicovaginal epithelium via epithelial ERalpha. 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.
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