Granger Katrina, Fitch Sarah, Shen May, Lloyd Jarrett, Bhurke Aishwarya, Hancock Jonathan, Ye Xiaoqin, Arora Ripla
Department of Obstetrics, Gynecology and Reproductive Biology, Michigan State University, East Lansing, MI, USA.
Institute for Quantitative Health Science and Engineering, Michigan State University, East Lansing, MI, USA.
Mol Hum Reprod. 2024 May 30;30(6). doi: 10.1093/molehr/gaae020.
Uterine glands are branched, tubular structures whose secretions are essential for pregnancy success. It is known that pre-implantation glandular expression of leukemia inhibitory factor (LIF) is crucial for embryo implantation; however, the contribution of uterine gland structure to gland secretions, such as LIF, is not known. Here, we use mice deficient in estrogen receptor 1 (ESR1) signaling to uncover the role of ESR1 signaling in gland branching and the role of a branched structure in LIF secretion and embryo implantation. We observed that deletion of ESR1 in neonatal uterine epithelium, stroma, and muscle using the progesterone receptor PgrCre causes a block in uterine gland development at the gland bud stage. Embryonic epithelial deletion of ESR1 using a Müllerian duct Cre line, Pax2Cre, displays gland bud elongation but a failure in gland branching. Reduction of ESR1 in adult uterine epithelium using the lactoferrin-Cre (LtfCre) displays normally branched uterine glands. Unbranched glands from Pax2Cre Esr1flox/flox uteri fail to express glandular pre-implantation Lif, preventing implantation chamber formation and embryo alignment along the uterine mesometrial-antimesometrial axis. In contrast, branched glands from LtfCre Esr1flox/flox uteri display reduced expression of ESR1 and glandular Lif resulting in delayed implantation chamber formation and embryo-uterine axes alignment but mice deliver a normal number of pups. Finally, pre-pubertal unbranched glands in control mice express Lif in the luminal epithelium but fail to express Lif in the glandular epithelium, even in the presence of estrogen. These data strongly suggest that branched glands are necessary for pre-implantation glandular Lif expression for implantation success. Our study is the first to identify a relationship between the branched structure and secretory function of uterine glands and provides a framework for understanding how uterine gland structure-function contributes to pregnancy success.
子宫腺是分支状的管状结构，其分泌物对妊娠成功至关重要。已知白血病抑制因子（LIF）在植入前的腺表达对胚胎着床至关重要；然而，子宫腺结构对诸如LIF等腺分泌物的贡献尚不清楚。在此，我们利用雌激素受体1（ESR1）信号缺失的小鼠来揭示ESR1信号在腺分支中的作用以及分支结构在LIF分泌和胚胎着床中的作用。我们观察到，使用孕激素受体PgrCre在新生小鼠子宫上皮、基质和肌肉中删除ESR1会导致子宫腺发育在腺芽阶段受阻。使用苗勒管Cre系Pax2Cre在胚胎上皮中删除ESR1会显示腺芽伸长，但腺分支失败。使用乳铁蛋白-Cre（LtfCre）在成年子宫上皮中降低ESR1表达，子宫腺显示正常分支。来自Pax2Cre Esr1flox/flox子宫的未分支腺未能表达植入前腺Lif，阻止了着床腔形成以及胚胎沿子宫系膜-反系膜轴排列。相比之下，来自LtfCre Esr1flox/flox子宫的分支腺ESR1和腺Lif表达降低，导致着床腔形成延迟和胚胎-子宫轴排列延迟，但小鼠产仔数正常。最后，对照小鼠青春期前的未分支腺在腔上皮中表达Lif，但即使在有雌激素的情况下，腺上皮中也不表达Lif。这些数据有力地表明，分支腺对于植入前腺Lif表达以实现着床成功是必要的。我们的研究首次确定了子宫腺分支结构与分泌功能之间的关系，并为理解子宫腺结构-功能如何促进妊娠成功提供了一个框架。
