Molecular signaling in uterine receptivity to implantation

摘要 人类的繁殖是复杂的，而且效率相当低。超过30%的受孕者 导致自然流产，大多数损失发生在 植入。这些不想要的怀孕损失导致了重大的心理问题， 经济上的，临床上的冲突。子宫环境不足是造成这种情况的原因之一。 失败--为了更深入地探索成功怀孕的机制，我们认识到 一个有能力的囊胚和接受者之间的有效双向互动 子宫是包括人类在内的胎盘哺乳动物着床的先决条件。这个 只有当这种分子对话建立起来时，胚泡才会被植入。通常， 小鼠的植入发生在一个特殊的植入腔(隐窝)内，该腔由 子宫腔上皮(LE)向子宫的反子宫(AM)侧外翻。 向AM形成均匀间隔的隐窝的基本机制 极地仍然难以捉摸。我们最近在小鼠身上的研究表明，受调控的Wnt5a-ROR 信号转导对着床和妊娠的建立至关重要。我们建议这一点 信号是由平面细胞极性(PCP)通过接触PCP组件来介导的 Vangl2、Scribble、Celsr1和Dvl2。我们将检验假设，五氯酚的活性在 与非规范Wnt5a-ROR信号的合作指导加密形成和 植入。目标1将测试子宫中主要的PCP信号成分是否活跃 大约在植入的时候。目标2将调查子宫PCP活性是否 通过使用遗传小鼠模型，对植入的隐窝形成至关重要。我们的 子宫缺失Vangl2(PCP核心成分)小鼠的初步结果 信号)显示植入缺陷和不良妊娠结局。这些 结果创造了一个独特的机会之窗，以产生分子和基因 子宫环境的潜在机制的信息 有利于胚泡在胚泡内归巢着床和妊娠 建制派。遗传的小鼠模型提供了与 女性生育能力在人类身上是不可行的。有很大的可能性 PCP信号在人类着床过程中起着重要作用，因为人类蛋白质组 Atlas记录了Vangl2、Vangl1和Wnt5a在人类子宫中的表达。 因此，收集有关PCP的机制和遗传证据是谨慎的。 在小鼠模型中对植入的要求，以更好地了解人类植入。

Summary Human reproduction is complex and fairly inefficient. More than 30% of conceptions result in spontaneous abortion with most losses occurring around the time of implantation. These unwanted pregnancy losses contribute to major psychological, economical, and clinical conflicts. Inadequate uterine milieu is one cause for this failure—to explore deeper into the mechanics of successful pregnancy, we recognize that effective two-way interactions between a competent blastocyst and the receptive uterus are a prerequisite for implantation in placental mammals including humans. The blastocyst will implant only when this molecular dialogue is established. Normally, implantation in mice occurs within a specialized implantation chamber (crypt) formed by luminal epithelial (LE) evaginations towards the antimesometrial (AM) side of the uterus. The underlying mechanism by which evenly spaced crypts are formed towards the AM pole remains elusive. Our recent work in mice shows that regulated Wnt5a-ROR signaling is critical to implantation and pregnancy establishment. We propose that this signaling is mediated by planar cell polarity (PCP) by engaging PCP components Vangl2, Scribble, Celsr1 and Dvl2. We will test the hypothesis that PCP activity in collaboration with non-canonical Wnt5a-ROR signaling directs crypt formation and implantation. Aim 1 will test if major PCP signaling constituents are active in the uterus around the time of implantation. Aim 2 will investigate whether uterine PCP activity is critical for crypt formation for implantation through the use of genetic mouse models. Our preliminary results in mice with uterine deletion of Vangl2 (a core component in PCP signaling) show defective implantation and compromised pregnancy outcomes. These results have created a unique window of opportunity to generate molecular and genetic information on a potential mechanism by which the uterine environment becomes conducive to blastocyst homing in the crypt for implantation and pregnancy establishment. The genetic mouse models provide mechanistic information relevant to female fertility which is not feasible to perform in humans. There is a strong possibility that PCP signaling plays a major role in human implantation, since the human proteome atlas has documented the expression of Vangl2, Vangl1 and Wnt5a in the human uterus. Thus, it is prudent to gather mechanistic and genetic evidence regarding PCP’s requirement in implantation in mouse models to better understand human implantation.