Bone morphogenetic protein 2 functions via a conserved signaling pathway involving Wnt4 to regulate uterine decidualization in the mouse and the human
Bone morphogenetic protein 2 functions via a conserved signaling pathway involving Wnt4 to regulate uterine decidualization in the mouse and the human
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DOI：
10.1074/jbc.m704723200
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发表时间：
2007-10-26
影响因子：
4.8
通讯作者：
Bagchi, Indrani C.
中科院分区：
文献类型：
--
作者：
Li, Quanxi;Kannan, Athilakshmi;Bagchi, Indrani C.
孕激素在妊娠早期的一个关键作用是诱导子宫内膜基质细胞分化为支持着床胚胎发育的特化蜕膜细胞。p诱导的信号通路参与蜕细胞的形成和功能仍然知之甚少。我们在此报道，骨形态发生蛋白2 （BMP2）的表达是TGF β超家族的一种形态因子，在小鼠子宫间质脱胞过程中诱导P作用的下游。为了确定BMP2在分化过程中的功能，我们采用了一种原代培养系统，在该系统中，从妊娠小鼠子宫分离的未分化间质细胞进行脱体细胞化。当重组BMP2加入到这些基质培养物中时，它显著地促进了分化程序。我们还发现sirna介导的BMP2表达沉默有效地阻断了这些细胞的分化过程。基因表达谱实验发现Wnt4是BMP2在脱个体化基质细胞中调控的下游靶点。通过sirna抑制Wnt4的表达大大降低了体外间质分化，表明它是bmp2诱导的脱细胞化的关键介质。我们还观察到，在体外对类固醇和cAMP的反应中，人子宫内膜基质细胞在脱胞过程中显著诱导BMP2的表达。在这些培养物中添加BMP2可显著增强Wnt4的表达并刺激分化过程。总的来说，我们的研究发现了一个独特的涉及BMP2和Wnt4的保守通路，介导小鼠和人类p诱导的间质去个体化。
A critical role of progesterone (P) during early pregnancy is to induce differentiation of the endometrial stromal cells into specialized decidual cells that support the development of the implanting embryo. The P-induced signaling pathways that participate in the formation and function of the decidual cells remain poorly understood. We report here that the expression of the bone morphogenetic protein 2 (BMP2), a morphogen belonging to the TGF beta superfamily, is induced downstream of P action in the mouse uterine stroma during decidualization. To determine the function of BMP2 during this differentiation process, we employed a primary culture system in which undifferentiated stromal cells isolated from pregnant mouse uterus undergo decidualization. When recombinant BMP2 was added to these stromal cultures, it markedly advanced the differentiation program. We also found that siRNA-mediated silencing of BMP2 expression in these cells efficiently blocked the differentiation process. Gene expression profiling experiments identified Wnt4 as a downstream target of BMP2 regulation in stromal cells undergoing decidualization. Attenuation of Wnt4 expression by siRNAs greatly reduced stromal differentiation in vitro, indicating that it is a key mediator of BMP2-induced decidualization. We also observed a remarkable induction in the expression of BMP2 in human endometrial stromal cells during decidualization in vitro in response to steroids and cAMP. Addition of BMP2 to these cultures led to a robust enhancement of Wnt4 expression and stimulated the differentiation process. Collectively, our studies uncovered a unique conserved pathway involving BMP2 and Wnt4 that mediates P-induced stromal decidualization in the mouse and the human.