Kurita Takeshi, Mills Alea A, Cunha Gerald R
Department of Anatomy, University of California, San Francisco, CA 94143-0452, USA.
Development. 2004 Apr;131(7):1639-49. doi: 10.1242/dev.01038. Epub 2004 Mar 3.
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 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.
子宫内接触己烯雌酚（DES）的女性会出现异常，包括可能导致癌症的宫颈阴道腺病。我们报告称，DES对发育信号的短暂干扰会永久性改变p63的表达，从而改变苗勒管上皮的发育命运。苗勒上皮细胞分化为柱状（子宫）或鳞状（宫颈阴道）的细胞命运是在围产期由间充质诱导决定的。宫颈阴道间充质在苗勒管上皮中诱导p63表达，随后发生鳞状分化。在p63基因敲除小鼠中，宫颈阴道上皮分化为子宫上皮。因此，p63是苗勒管上皮细胞向宫颈阴道或子宫方向分化的身份转换因子。P63对于DES暴露诱导的子宫鳞状化生也至关重要。出生后第1天至第5天暴露于DES会通过上皮雌激素受体α抑制宫颈阴道上皮中p63的诱导。DES的抑制作用是短暂的，在停止DES治疗后2天，大多数宫颈阴道上皮细胞恢复了p63的表达。然而，一些宫颈阴道上皮细胞未能表达p63，仍为柱状，并作为腺病持续到成年期。
