Kelleher Andrew M, Peng Wang, Pru James K, Pru Cindy A, DeMayo Francesco J, Spencer Thomas E
Division of Animal Sciences, University of Missouri, Columbia, MO 65211.
Department of Animal Sciences, Washington State University, Pullman, WA 99164.
Proc Natl Acad Sci U S A. 2017 Feb 7;114(6):E1018-E1026. doi: 10.1073/pnas.1618433114. Epub 2017 Jan 3.
Establishment of pregnancy is a critical event, and failure of embryo implantation and stromal decidualization in the uterus contribute to significant numbers of pregnancy losses in women. Glands of the uterus are essential for establishment of pregnancy in mice and likely in humans. Forkhead box a2 (FOXA2) is a transcription factor expressed specifically in the glands of the uterus and is a critical regulator of postnatal uterine gland differentiation in mice. In this study, we conditionally deleted FOXA2 in the adult mouse uterus using the lactotransferrin Cre (Ltf-Cre) model and in the neonatal mouse uterus using the progesterone receptor Cre (Pgr-Cre) model. The uteri of adult FOXA2-deleted mice were morphologically normal and contained glands, whereas the uteri of neonatal FOXA2-deleted mice were completely aglandular. Notably, adult FOXA2-deleted mice are completely infertile because of defects in blastocyst implantation and stromal cell decidualization. Leukemia inhibitory factor (LIF), a critical implantation factor of uterine gland origin, was not expressed during early pregnancy in adult FOXA2-deleted mice. Intriguingly, i.p. injections of LIF initiated blastocyst implantation in the uteri of both gland-containing and glandless adult FOXA2-deleted mice. Although pregnancy was rescued by LIF and was maintained to term in uterine gland-containing adult FOXA2-deleted mice, pregnancy failed by day 10 in neonatal FOXA2-deleted mice lacking uterine glands. These studies reveal a previously unrecognized role for FOXA2 in regulation of adult uterine function and fertility and provide original evidence that uterine glands and, by inference, their secretions play important roles in blastocyst implantation and stromal cell decidualization.
妊娠的建立是一个关键事件，胚胎植入失败和子宫基质蜕膜化导致大量女性妊娠丢失。子宫腺体对小鼠及可能对人类的妊娠建立至关重要。叉头框a2（FOXA2）是一种在子宫腺体中特异性表达的转录因子，是小鼠出生后子宫腺体分化的关键调节因子。在本研究中，我们使用乳铁传递蛋白Cre（Ltf-Cre）模型在成年小鼠子宫中条件性敲除FOXA2，并使用孕酮受体Cre（Pgr-Cre）模型在新生小鼠子宫中条件性敲除FOXA2。成年FOXA2敲除小鼠的子宫形态正常且含有腺体，而新生FOXA2敲除小鼠的子宫完全无腺体。值得注意的是，成年FOXA2敲除小鼠由于囊胚植入和基质细胞蜕膜化缺陷而完全不育。白血病抑制因子（LIF）是一种源自子宫腺体的关键植入因子，在成年FOXA2敲除小鼠的妊娠早期不表达。有趣的是，腹腔注射LIF可启动含腺体和无腺体成年FOXA2敲除小鼠子宫中的囊胚植入。尽管LIF挽救了妊娠并使含子宫腺体的成年FOXA2敲除小鼠维持到足月，但缺乏子宫腺体的新生FOXA2敲除小鼠在第10天时妊娠失败。这些研究揭示了FOXA2在调节成年子宫功能和生育能力方面以前未被认识的作用，并提供了原始证据，表明子宫腺体及其分泌物在囊胚植入和基质细胞蜕膜化中起重要作用。
