MSX2 promotes vaginal epithelial differentiation and wolffian duct regression and dampens the vaginal response to diethylstilbestrol.
MSX2 promotes vaginal epithelial differentiation and wolffian duct regression and dampens the vaginal response to diethylstilbestrol.
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DOI：
10.1210/me.2005-0451
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发表时间：
2006-07
影响因子：
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通讯作者：
Yan Yin;Congxing Lin;Liang Ma
中科院分区：
文献类型：
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作者：
Yan Yin;Congxing Lin;Liang Ma
子宫内暴露于己烯雌酚（DES）导致女性生殖道（FRT）的图案缺陷和人类阴道腺癌发展的倾向。在小鼠中，DES治疗类似地诱导过多的FRT发育缺陷，包括子宫上皮分层以及子宫颈和阴道中存在腺组织。子宫异常与同源异型盒基因Msx2的抑制有关，DES导致Msx2突变体的子宫反应改变，包括子宫腔扩张。在这里，我们研究Msx2在正常阴道发育和DES的FRT反应中的作用。在阴道发育过程中，Msx2是Tgf β 2和Tgf β 3表达以及适当的阴道上皮分化所必需的。此外，Msx2通过促进细胞凋亡参与尾侧沃尔夫管退化。一致的，新生儿DES暴露抑制Msx2表达的Wolffian管上皮细胞，抑制其凋亡和随后的回归。有趣的是，虽然DES治疗也抑制Msx2在阴道上皮中的表达，但在Msx2突变小鼠中观察到更严重的DES诱导的阴道表型，包括苗勒氏阴道上皮分层的完全失败和严重扩张的阴道腔，伴随着p63和水通道蛋白表达的丧失。这些结果表明Msx2在抵消DES对FRT模式的影响中起着关键作用，并表明对DES的反应可能因个体的基因型而高度可变。
In utero exposure to diethylstilbestrol (DES) leads to patterning defects in the female reproductive tract (FRT) and a propensity to the development of vaginal adenocarcinomas in humans. In the mouse, DES treatment similarly induces a plethora of FRT developmental defects, including stratification of uterine epithelium and presence of glandular tissue in cervix and vagina. Uterine abnormalities are associated with repression of the homeobox gene Msx2, and DES leads to an altered uterine response in Msx2 mutants including a dilated uterine lumen. Here we investigate the role of Msx2 in normal vaginal development and in FRT response to DES. During vaginal development, Msx2 is required for Tgfbeta2 and Tgfbeta3 expression and for proper vaginal epithelial differentiation. Moreover, Msx2 is involved in caudal Wolffian duct regression by promoting apoptosis. Consistently, neonatal DES exposure represses Msx2 expression in the Wolffian duct epithelium and inhibits its apoptosis and subsequent regression. Intriguingly, although DES treatment also represses Msx2 expression in the vaginal epithelium, a much more severe DES-induced vaginal phenotype was observed in Msx2 mutant mice, including a complete failure of Müllerian vaginal epithelial stratification and a severely dilated vaginal lumen, accompanied by loss of p63 and water channel protein expression. These results demonstrate a critical role for Msx2 in counteracting the effect of DES on FRT patterning and suggest that the response to DES may be highly variable depending on the genotype of an individual.