CTNNB1 in Mesenchyme Regulates Epithelial Cell Differentiation during Mullerian Duct and Postnatal Uterine Development
CTNNB1 in Mesenchyme Regulates Epithelial Cell Differentiation during Mullerian Duct and Postnatal Uterine Development
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DOI：
10.1210/me.2012-1126
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发表时间：
2013-09-01
影响因子：
--
通讯作者：
Behringer, Richard R.
中科院分区：
文献类型：
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作者：
Stewart, C. Allison;Wang, Ying;Behringer, Richard R.
苗勒管分化和发育为女性生殖道是生育力所必需的，但调节这些过程的机制知之甚少。WNT信号传导对于雌性生殖道的正常发育至关重要，如Wnt 4、Wnt 5a、Wnt 7a和β-连环蛋白（Ctnnb 1）突变小鼠的表型所示。在这里，我们扩展这些发现，通过确定的影响，组成CTNNB 1激活的间充质内的发展中的苗勒管及其分化的衍生物。这是通过将Amhr 2-Cre敲入小鼠与Ctnnb 1外显子（ex）3（f/f）小鼠杂交来实现的。Amhr 2-Cre（Delta/+）; Ctnnb 1 ex 3（f/+）雌性未形成输卵管，子宫较小，子宫内膜腺缺陷，并且不育。在细胞水平，CTNNB 1在间充质中的稳定引起上皮内的改变，包括增殖减少、子宫腺形成延迟和上皮-间充质转化（EMT）事件的诱导。这种EMT事件在出生前观察到，并在出生后5天内完成。出生前上皮细胞雌激素受体α表达异常与EMT相关，出生后EMT与EMT无关。这些研究表明，在女性生殖道发育过程中，间充质中受调节的CTNNB 1对上皮细胞分化很重要。
Mullerian 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 beta-catenin (Ctnnb1) mutant mice. Here we extend these findings by determining the effects of constitutive CTNNB1 activation within the mesenchyme of the developing Mullerian 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(Delta/+); 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 alpha 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.