Department of Molecular and Cellular Biology, Department of Molecular and Human Genetics, The Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas 77030, USA.
Biol Reprod. 2010 May;82(5):991-9. doi: 10.1095/biolreprod.109.081513. Epub 2010 Feb 3.
Previous work has identified Indian hedgehog (Ihh) as a major mediator of progesterone signaling during embryo implantation. Ihh acts through its downstream effector smoothened (Smo) to activate the GLI family of transcription factors. In order to gain a better understanding of Ihh action during embryo implantation, we expressed a Cre-recombinase-dependent constitutively activated SMO in the murine uterus using the Pgr(tm2(cre)Lyd) (PR(cre)) mouse model [Pgr(tm2(cre)Lyd+)Gt(ROSA)26Sor(tm1(Smo/EYFP)Amc)(+) (PR(cre/+)SmoM2(+))]. Female PR(cre/+)SmoM2(+) mice were infertile. They exhibited normal serum progesterone levels and normal ovulation, but their ova failed to be fertilized in vivo and their uterus failed to undergo the artificially induced decidual response. Examination of the PR(cre/+)SmoM2(+) uteri revealed numerous features such as uterine hypertrophy, the presence of a stratified luminal epithelial cell layer, a reduced number of uterine glands, and an endometrial stroma that had lost its normal morphologic characteristics. Microarray analysis of 3-mo-old PR(cre/+)SmoM2(+) uteri demonstrated a chondrocytic signature and confirmed that constitutive activation of PR(cre/+)SmoM2(+) increased extracellular matrix production. Thus, constitutive activation of Smo in the mouse uterus alters postnatal uterine differentiation which interferes with early pregnancy. These results provide new insight into the role of Hedgehog signaling during embryo implantation.
先前的研究已经确定，印度刺猬（Ihh）是胚胎植入过程中孕激素信号的主要介质。Ihh 通过其下游效应物 smoothened（Smo）起作用，激活 GLI 家族转录因子。为了更好地了解胚胎植入过程中 Ihh 的作用，我们使用 Pgr(tm2(cre)Lyd)（PR(cre)）小鼠模型在小鼠子宫中表达了一种依赖 Cre 重组酶的组成型激活 Smo。[Pgr(tm2(cre)Lyd+)Gt(ROSA)26Sor(tm1(Smo/EYFP)Amc)(+)（PR(cre/+)SmoM2(+))]。雌性 PR(cre/+)SmoM2(+) 小鼠不育。它们表现出正常的血清孕激素水平和正常排卵，但它们的卵子在体内未能受精，它们的子宫未能经历人工诱导的蜕膜反应。对 PR(cre/+)SmoM2(+)子宫的检查显示出许多特征，如子宫肥大、存在分层的腔上皮细胞层、子宫腺数量减少以及子宫内膜基质失去了正常的形态特征。对 3 个月大的 PR(cre/+)SmoM2(+)子宫的微阵列分析显示出软骨细胞特征，并证实 PR(cre/+)SmoM2(+)的组成型激活增加了细胞外基质的产生。因此，Smom 在小鼠子宫中的组成型激活改变了产后子宫分化，干扰了早期妊娠。这些结果为 Hedgehog 信号在胚胎植入过程中的作用提供了新的见解。
