Constitutive Activation of Smoothened Leads to Female Infertility and Altered Uterine Differentiation in the Mouse
Constitutive Activation of Smoothened Leads to Female Infertility and Altered Uterine Differentiation in the Mouse
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DOI：
10.1095/biolreprod.109.081513
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发表时间：
2010-05-01
影响因子：
3.6
通讯作者：
DeMayo, Francesco J.
中科院分区：
文献类型：
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作者：
Franco, Heather L.;Lee, Kevin Y.;DeMayo, Francesco J.
以前的工作已经确定印度刺猬（Ihh）作为一个主要的调解人的孕激素信号在胚胎植入。Ihh通过其下游效应子smoothened（Smo）激活GLI家族的转录因子。为了更好地理解Ihh在胚胎植入期间的作用，我们使用Pgr（tm 2（cre）Lyd）（PRcre）小鼠模型[Pgr（tm 2（cre）Lyd+）Gt（ROSA）26 Sor（tm 1（Smo/EYFP）Amc+）（PR（cre/+）SmoM 2（+））]在小鼠子宫中表达Cre重组酶依赖性组成型激活的SMO。雌性PR（cre/+）SmoM 2（+）小鼠不育。他们表现出正常的血清孕酮水平和正常排卵，但他们的卵子未能在体内受精，他们的子宫未能经历人工诱导的蜕膜反应。PR（cre/+）SmoM 2（+）子宫的检查显示了许多特征，如子宫肥大，存在分层的腔上皮细胞层，子宫腺体数量减少，子宫内膜基质失去了正常的形态学特征。3月龄PR（cre/+）SmoM 2（+）子宫的微阵列分析显示了软骨细胞的特征，并证实PR（cre/+）SmoM 2（+）的组成性激活增加了细胞外基质的产生。因此，组成性激活的Smo在小鼠子宫改变出生后的子宫分化，干扰早期妊娠。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。
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) (PRcre) 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.