Msx2 Promotes Vaginal Epithelial Differentiation and Wolffian Duct Regression and Dampens the Vaginal Response to Diethylstilbestrol

Abstract

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.

Induction of mammary gland ductal hyperplasias and carcinoma in situ following fetal bisphenol A exposure

“…More recently, msx2 which plays a critical role in cell fate determination in the vaginal epithelium, was shown to be repressed by DES [58]. This homeodomain transcription factor is required for the correct expression of wnt7a, and the absence of msx2 would result in a complete failure of stratification of the vaginal epithelium [59].…”

Essential role of the CUL4B ubiquitin ligase in extra-embryonic tissue development during mouse embryogenesis

“…Whole mount IF on blastocysts was performed as previously described [39]. Standard IF was performed on PFA-fixed paraffin sections (6 µm) (E5.0) or frozen sections (E7.5) following procedures as previously described [40]. Immunohistochemistry was performed on paraffin-embedded embryo sections as previously described in detail [12].…”

The developing female genital tract: from genetics to epigenetics

“…In this context of reciprocal interactions, p63, a homologue of p53 tumour suppressor gene, is considered as an identity switch for MD epithelial differentiation into uterine or cervicovaginal cell fate (Ince et al 2002;Kurita et al 2004). Besides, the homeodomain transcription factor Msx2, promotes normal vaginal epithelial differentiation and, interestingly, seems to be involved in regression of the caudal region of WD in females by promoting apoptosis (Yin et al 2006).In conclusion, differentiation of MD into a functional reproductive tract relies on a complex genetic cascade wherein cooperation between Wnt and Hox genes is fundamental for correct patterning and maturation of the FRT. It is noteworthy that many of the developmental genes presented above, especially Hox genes, are also regulated by steroid hormones during both embryogenesis and adulthood (Daftary and Taylor 2006).…”