子宫腺体是分支管状结构，其分泌物对于成功妊娠至关重要。众所周知，白血病抑制因子（LIF）的植入前腺体表达对于胚胎植入至关重要，但是子宫腺体结构对腺体分泌物（例如LIF）的贡献尚不清楚。在这里，我们使用雌激素受体 1 (ESR1) 信号缺陷的小鼠来揭示 ESR1 信号在腺体分支中的作用以及分支结构在 LIF 分泌和胚胎植入中的作用。我们观察到，使用孕酮受体 PgrCre 删除新生儿子宫上皮、间质和肌肉中的 ESR1 会导致腺芽阶段子宫腺体发育受阻。使用苗勒氏管 Cre 系 Pax2Cre 进行 ESR1 的胚胎上皮缺失，显示腺芽伸长，但腺体分支失败。使用乳铁蛋白-Cre (LtfCre) 减少成人子宫上皮中的 ESR1，显示出正常分支的子宫腺体。来自 Pax2Cre Esr1flox/flox uteri 的无分支腺体无法表达腺体植入前 Lif，从而阻止着床室形成和胚胎沿子宫中膜-抗时膜轴排列。相比之下，来自 LtfCre Esr1flox/floxuteri 的分支腺体显示 ESR1 和腺体 Lif 的表达减少，导致着床室形成延迟和胚胎-子宫轴对齐，但小鼠产下的幼崽数量正常。最后，对照小鼠的青春期前无分支腺体在管腔上皮中表达Lif，但即使在雌激素存在的情况下也不能在腺上皮中表达Lif。这些数据强烈表明，分支腺体对于植入前腺体 Lif 表达以实现植入成功是必需的。我们的研究首次确定了子宫腺体的分支结构和分泌功能之间的关系，并为理解子宫腺体结构功能如何有助于妊娠成功提供了一个框架。© 作者 2024 年。由牛津大学出版社出版代表欧洲人类生殖和胚胎学学会。

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/floxuteri 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.© The Author(s) 2024. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology.