Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030.
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030.
Proc Natl Acad Sci U S A. 2017 Jun 13;114(24):E4772-E4781. doi: 10.1073/pnas.1620903114. Epub 2017 May 30.
Embryo implantation remains a significant challenge for assisted reproductive technology, with implantation failure occurring in ∼50% of in vitro fertilization attempts. Understanding the molecular mechanisms underlying uterine receptivity will enable the development of new interventions and biomarkers. TGFβ family signaling in the uterus is critical for establishing and maintaining pregnancy. Follistatin (FST) regulates TGFβ family signaling by selectively binding TGFβ family ligands and sequestering them. In humans, FST is up-regulated in the decidua during early pregnancy, and women with recurrent miscarriage have lower endometrial expression of FST during the luteal phase. Because global knockout of is perinatal lethal in mice, we generated a conditional knockout (cKO) of in the uterus using progesterone receptor-cre to study the roles of uterine during pregnancy. Uterine -cKO mice demonstrate severe fertility defects and deliver only 2% of the number of pups delivered by control females. In -cKO mice, the uterine luminal epithelium does not respond properly to estrogen and progesterone signals and remains unreceptive to embryo attachment by continuing to proliferate and failing to differentiate. The uterine stroma of -cKO mice also responds poorly to artificial decidualization, with lower levels of proliferation and differentiation. In the absence of uterine FST, activin B expression and signaling are up-regulated, and bone morphogenetic protein (BMP) signals are impaired. Our findings support a model in which repression of activin signaling by FST enables uterine receptivity by preserving critical BMP signaling.
胚胎着床仍然是辅助生殖技术的一个重大挑战，体外受精尝试中约有 50% 会着床失败。了解子宫容受性的分子机制将能够开发新的干预措施和生物标志物。子宫内 TGFβ 家族信号对于建立和维持妊娠至关重要。卵泡抑素 (FST) 通过选择性结合 TGFβ 家族配体并将其隔离来调节 TGFβ 家族信号。在人类中，FST 在妊娠早期的蜕膜中上调，而复发性流产的女性在黄体期的子宫内膜中 FST 表达水平较低。由于 基因在小鼠中敲除会导致围产期致死，因此我们使用孕激素受体-cre 生成了子宫内的条件性敲除 (cKO) ，以研究怀孕期间子宫内 基因的作用。子宫 -cKO 小鼠表现出严重的生育缺陷，只能产下对照组雌鼠产仔数的 2%。在 -cKO 小鼠中，子宫腔上皮对雌激素和孕激素信号没有适当反应，继续增殖而不分化，因此对胚胎附着没有反应。-cKO 小鼠的子宫基质对人工蜕膜化的反应也很差，增殖和分化水平较低。在缺乏子宫 FST 的情况下，激活素 B 的表达和信号被上调，骨形态发生蛋白 (BMP) 信号受损。我们的研究结果支持这样一种模型，即 FST 通过抑制激活素信号来维持关键的 BMP 信号，从而使子宫具有容受性。
