Molecular signaling in uterine receptivity to implantation

胚胎植入是怀孕成功的一个途径。胚泡和胚胎之间的相互作用 子宫对着床至关重要健康的植入室（隐窝）的形成对于 正常的胚胎植入;不正常的隐窝导致生育力低下。平面电池极性（PCP）是一种 非经典Wnt 5a信号通路的经典下游靶点。子宫缺失旺- 如蛋白质2（Vangl 2），PCP的主要成分，严重破坏隐窝形成，胚胎间隔， 和蜕膜化，最终影响妊娠结果。我们发现地下室 总是起源于预先存在的腺体， 胚泡和腺体。肝素结合EGF样生长因子（HB-EGF） 在胚泡周围的隐窝上皮中，如果转移， 到第4天的假孕子宫，引起类似于正常妊娠的流产样变化。 然而，这些反应未能发生在缺失Vangl 2的子宫中，表明Vangl 2的交叉 HB-EGF信号HB-EGF通过EGF受体家族（Erbbs 1-4）发挥作用。 作为同二聚体或异二聚体并诱导酪氨酸磷酸化。这个提案将测试一部小说 假设HB-EGF信号与PCP信号通过使ErbB参与 置入通过ErbBs 1-4起作用的HB-EGF诱导酪氨酸磷酸化。我们的初步 结果显示Vangl 2与ErbB 2和ErbB 3的物理关联，表明这些 受体，如果被HB-EGF激活，转磷酸化Vangl 2。以下两个具体目标将 使用小鼠模型研究PCP和HB-EGF信号在植入中的相互作用： 具体目标1将检验HB-EGF信号传导与Vangl 2信号传导交叉以指导Vangl 2信号传导的假设。 形成适当的腺体-隐窝组件，用于植入物之间的直接串扰， 囊胚和腺体。这两种不同信号通路的互锁涉及 ErbB受体家族成员的磷酸化，随后是ErbB受体家族成员的转磷酸化。 Vangl2.具体目标2将检验HB-EGF和Vangl 2的功能性偶联 着床中的信号传导需要子宫上皮中存在ErbB 1、ErbB 2和/或ErbB 3 和/或基质。我们将使用Pgr-Cre和Ltf对ErbB 1、ErbB 2和/或ErbB 3进行条件删除。 iCre驱动器来探索子宫中的Vangl 2磷酸化状态，并将这些结果与子宫中的Vangl 2磷酸化状态相关联。 妊娠表型这个项目的成功完成将揭示一个概念属性， 生长因子信号通路与PCP交叉的着床和妊娠生物学领域 在形成植入腔（隐窝）以成功怀孕中的信号传导。

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.