Molecular signaling in uterine receptivity to implantation

胚胎植入是妊娠成功的一个途径。胚泡和胚泡之间的串音 子宫对着床至关重要。形成一个健康的种植室(隐窝)对于 正常的胚胎植入；不正常的隐窝会导致不育。平面细胞极性(PCP)是一种 非典型Wnt5a信号通路的经典下游靶点。子宫缺失的Vang- 像PCP的主要成分蛋白2(Vangl2)一样，它严重破坏了隐窝的形成，胚胎的间隔， 和蜕膜化，最终影响妊娠结局。我们已经找到了那个墓穴 总是起源于预先存在的腺体，赋予植入之间的直接联系 胚泡和腺体。肝素结合的表皮生长因子样生长因子(HB-EGF)被特异性表达 在囊胚周围的隐窝上皮细胞中，以及预载有HB-EGF的珠子，如果转移的话 至假孕第4天，可引起与正常妊娠相似的着床样改变。 然而，这些反应在缺失Vangl2的子宫中未能发生，这表明Vangl2存在交集 带有HB-EGF信号。HB-EGF通过EGF受体家族(ERBBS 1-4)发挥作用 作为同源二聚体或异源二聚体，并诱导酪氨酸磷酸化。这项提议将考验一部小说 假设HB-EGF信号与PCP信号通过参与ERBBS参与 植入。HB-EGF通过ERBBS 1-4作用诱导酪氨酸磷酸化。我们的预赛 结果显示Vangl2与ErbB2和ErbB3存在物理联系，表明这些 受体，如果被HB-EGF激活，转磷酸Vangl2。以下两个具体目标将 利用小鼠模型研究PCP和HB-EGF信号在着床过程中的相互作用： 特定目标1将检验HB-EGF信号与Vangl2信号相交的假设 形成合适的腺体-隐窝组件，用于种植体之间的直接串扰 胚泡和腺体。这两条不同信号通路的联锁包括 ErbB受体家族成员的磷酸化和转磷酸化 Vangl2.特异靶2将检验HB-EGF和Vangl2功能偶联的假设 着床信号需要子宫上皮中存在ErbB1、ErbB2和/或ErbB3 和/或基质。我们将使用PGR-CRE和LTF-对ErbB1、ErbB2和/或ErbB3进行条件删除 ICre驱动程序来探索子宫中Vangl2的磷酸化状态，并将这些结果与 妊娠表型。该项目的成功完成将揭示出 生长因子信号通路与PCP交叉的植入和妊娠生物学领域 妊娠成功形成着床腔(窝)的信号传递。

Embryo implantation is a gateway to pregnancy success. A crosstalk between the blastocyst and uterus is vital to implantation. Formation of a healthy implantation chamber (crypt) is critical for normal embryo implantation; an abnormal crypt results in subfertility. Planar cell polarity (PCP) is a classic downstream target of the non-canonical Wnt5a signaling pathway. Uterine deletion of Vang- like protein 2 (Vangl2), a major PCP component, severely derails crypt formation, embryo spacing, and decidualization, ultimately compromising pregnancy outcomes. We have found that crypts invariably originate with preexisting glands conferring direct communication between the implanting blastocyst and glands. Heparin-binding EGF-like growth factor (HB-EGF) is exclusively expressed in the crypt epithelium surrounding the blastocyst, and beads preloaded with HB-EGF, if transferred to day 4 pseudopregnant uteri, evoke implantation-like changes similar to normal pregnancy. However, these responses fail to occur in uteri missing Vangl2, suggesting an intersection of Vangl2 with HB-EGF signaling. HB-EGF executes its function via the EGF family of receptors (Erbbs 1-4) as homodimers or heterodimers and induces tyrosine phosphorylation. This proposal will test a novel hypothesis that HB-EGF signaling intersects with PCP signaling by engaging the ErbBs in implantation. HB-EGF working via ErbBs 1-4 induces tyrosine phosphorylation. Our preliminary results show a physical association of Vangl2 with ErbB2 and ErbB3, suggesting that these receptors, if activated by HB-EGF, transphosphorylate Vangl2. The following two specific aims will study interactions between PCP and HB-EGF signaling in implantation using mouse models: Specific aim 1 will test the hypothesis that HB-EGF signaling intersects with Vangl2 signaling to direct the formation of an appropriate glands-crypt assembly for direct cross-talk between the implanting blastocyst and the glands. This interlocking of two different signaling pathways involves phosphorylation of members of the ErbB family of receptors followed by transphosphorylation of Vangl2. Specific aim 2 will test the hypothesis that the functional coupling of HB-EGF and Vangl2 signaling in implantation requires the presence of ErbB1, ErbB2 and/or ErbB3 in the uterine epithelium and/or stroma. We will use conditional deletion of ErbB1, ErbB2 and/or ErbB3 using Pgr-Cre and Ltf- iCre drivers to explore the Vangl2 phosphorylation status in the uterus, and correlate these results with pregnancy phenotypes. Successful completion of this project will reveal a conceptual attribute to the field of implantation and pregnancy biology that a growth factor signaling pathway intersects with PCP signaling in forming implantation chambers (crypts) for pregnancy success.