Hewitt Damien P, Mark Peter J, Dharmarajan Arun M, Waddell Brendan J
School of Anatomy and Human Biology, The University of Western Australia, Perth, Western Australia 6009, Australia.
Biol Reprod. 2006 Jul;75(1):75-81. doi: 10.1095/biolreprod.105.047647. Epub 2006 Mar 15.
Wnt genes regulate a diverse range of developmental processes, including placental formation. Activation of the WNT pathway results in translocation of beta-catenin (CTNNB1) into the nucleus and the subsequent activation of transcription factors that promote proliferation. The secreted frizzled related proteins (SFRPs) are thought to inhibit WNT signaling by binding to the WNT ligand or its frizzled receptor. In this study, we compared the expression patterns of one of these secreted molecules, SFRP4, in the two morphologically and functionally distinct regions of the rat placenta during the last third of pregnancy. In addition, we assessed whether placental SFRP4 expression is altered in a model of glucocorticoid-induced placental growth restriction. Temporal analyses of the rat placenta by quantitative RT-PCR, in situ hybridization, and immunohistochemistry during the final third of pregnancy demonstrated elevated levels of Sfrp4 mRNA and SFRP4 protein near term, specifically in trophoblast cells of the basal zone. This increase in expression of SFRP4 in basal zone trophoblasts was associated with a reduction in CTNNB1 nuclear translocation, consistent with inhibition of the WNT pathway. Maternal dexamethasone treatment (1 microg/ml of drinking water, Days 13-22), which has previously been shown to reduce placental growth, further increased the expression of Sfrp4 mRNA in both the basal and labyrinth zones of the placenta at Day 22. Collectively, these data demonstrate that increased expression of SFRP4 is associated with reduced growth of placental regions in normal pregnancy and after glucocorticoid-induced growth retardation. These observations, together with associated changes in CTNNB1 localization, support the hypothesis that increased placental expression of SFRP4 inhibits the WNT pathway and thereby influences placental growth via effects on cell fate signaling.
Wnt基因调控多种发育过程，包括胎盘形成。WNT信号通路的激活导致β-连环蛋白（CTNNB1）易位至细胞核，并随后激活促进增殖的转录因子。分泌型卷曲相关蛋白（SFRPs）被认为通过与WNT配体或其卷曲受体结合来抑制WNT信号传导。在本研究中，我们比较了妊娠最后三分之一期间大鼠胎盘两个形态和功能不同区域中这些分泌分子之一SFRP4的表达模式。此外，我们评估了在糖皮质激素诱导的胎盘生长受限模型中胎盘SFRP4表达是否发生改变。在妊娠最后三分之一期间通过定量RT-PCR、原位杂交和免疫组织化学对大鼠胎盘进行的时间分析表明，足月时Sfrp4 mRNA和SFRP4蛋白水平升高，特别是在基底层的滋养层细胞中。基底层滋养层细胞中SFRP4表达的增加与CTNNB1核易位的减少相关，这与WNT信号通路的抑制一致。母体地塞米松治疗（1微克/毫升饮用水，第13 - 22天），此前已证明可减少胎盘生长，在第22天时进一步增加了胎盘基底层和迷路区Sfrp4 mRNA的表达。总体而言，这些数据表明，SFRP4表达增加与正常妊娠及糖皮质激素诱导的生长迟缓后胎盘区域生长减少有关。这些观察结果以及CTNNB1定位的相关变化支持了以下假设，即胎盘SFRP4表达增加会抑制WNT信号通路，从而通过影响细胞命运信号传导来影响胎盘生长。
