Stewart C Allison, Wang Ying, Bonilla-Claudio Margarita, Martin James F, Gonzalez Gabriel, Taketo Makoto M, Behringer Richard R
Department of Genetics, University of Texas MD Anderson Cancer Center, University of Texas Graduate School of Biomedical Sciences, Houston, Texas 77030, USA.
Mol Endocrinol. 2013 Sep;27(9):1442-54. doi: 10.1210/me.2012-1126. Epub 2013 Jul 31.
Müllerian duct differentiation and development into the female reproductive tract is essential for fertility, but mechanisms regulating these processes are poorly understood. WNT signaling is critical for proper development of the female reproductive tract as evident by the phenotypes of Wnt4, Wnt5a, Wnt7a, and β-catenin (Ctnnb1) mutant mice. Here we extend these findings by determining the effects of constitutive CTNNB1 activation within the mesenchyme of the developing Müllerian duct and its differentiated derivatives. This was accomplished by crossing Amhr2-Cre knock-in mice with Ctnnb1 exon (ex) 3(f/f) mice. Amhr2-Cre(Δ/+); Ctnnb1 ex3(f/+) females did not form an oviduct, had smaller uteri, endometrial gland defects, and were infertile. At the cellular level, stabilization of CTNNB1 in the mesenchyme caused alterations within the epithelium, including less proliferation, delayed uterine gland formation, and induction of an epithelial-mesenchymal transition (EMT) event. This EMT event is observed before birth and is complete within 5 days after birth. Misexpression of estrogen receptor α in the epithelia correlated with the EMT before birth, but not after. These studies indicate that regulated CTNNB1 in mesenchyme is important for epithelial cell differentiation during female reproductive tract development.
苗勒管分化并发育为女性生殖道对生育能力至关重要，但调控这些过程的机制仍知之甚少。WNT信号通路对女性生殖道的正常发育至关重要，这在Wnt4、Wnt5a、Wnt7a和β-连环蛋白（Ctnnb1）突变小鼠的表型中得到了体现。在此，我们通过确定持续激活CTNNB1对发育中的苗勒管及其分化衍生物间充质的影响来扩展这些发现。这是通过将Amhr2-Cre基因敲入小鼠与Ctnnb1外显子（ex）3（f/f）小鼠杂交来实现的。Amhr2-Cre（Δ/+）；Ctnnb1 ex3（f/+）雌性小鼠未形成输卵管，子宫较小，存在子宫内膜腺体缺陷，且不育。在细胞水平上，间充质中CTNNB1的稳定导致上皮内发生改变，包括增殖减少、子宫腺体形成延迟以及诱导上皮-间充质转化（EMT）事件。这种EMT事件在出生前即可观察到，并在出生后5天内完成。出生前上皮中雌激素受体α的错误表达与EMT相关，但出生后则不然。这些研究表明，间充质中受调控的CTNNB1对女性生殖道发育过程中的上皮细胞分化很重要。
