Regulation of cell polarity by Wnt signaling

这一建议涉及调控上皮细胞方向的信号机制。 脊椎动物胚胎中的平面，称为平面细胞极性(PCP)。这很常见 这一现象是由一组保守的蛋白质介导的，这些蛋白质极化到 组织中的一种上皮细胞。分泌的Wnt蛋白与控制有关 但Wnt蛋白是否以及如何向PCP提供定向输入 系统仍不清楚。我们的实验室对WNT信号和WNT信号有长期的兴趣 细胞极性，但机制研究因缺乏易处理的模型和 合适的分子标记。最近，我们小组开发了特定的抗体和 荧光传感器用于PCP分析，并发现了细胞的独特极性 非洲爪哇原肠表皮和神经板。拟议的研究将使用新的 解决以下继续挑战该领域的关键问题的工具。答：什么？ 极化细胞中核心PCP蛋白分离的机制？胡麻B. 控制PCP的空间线索或信号是什么？C.细胞极化是如何 转化为形态发生细胞行为？我们的实验将揭开分子 PCP核心蛋白Vangl2对前根尖极化的调节机制 非洲爪哇的细胞边缘。其他研究将阐明Wnt配体在这一过程中的作用 利用基于质谱学的方法处理和鉴定在五氯酚中起作用的新蛋白质 接近了。这些实验将使用非洲爪哇胚胎，这是一种独特的体内模型，在 哪些生化、胚胎学和细胞生物学方法可以结合起来。这个 拟议的研究将促进对基本细胞生物学机制的了解 脊椎动物的早期形态发生事件，如原肠形成和神经形成。 由于Wnt和PCP信号的错误调节与许多 先天性缺陷和综合征、多囊肾病和多发性癌症， 这些研究与人类健康高度相关。

This proposal concerns signaling mechanisms regulating cell orientation in the epithelial plane in the vertebrate embryo that is known as planar cell polarity (PCP). This common phenomenon is mediated by a group of conserved proteins that polarize to one side of an epithelial cell in the tissue. Secreted Wnt proteins have been implicated in the control of PCP, but whether and how Wnt proteins provide the directional input to the PCP system remains unclear. Our laboratory has a long-term interest in Wnt signaling and cell polarity, but mechanistic studies were hampered by lack of tractable models and suitable molecular markers. Recently, our group has developed specific antibodies and fluorescent sensors for PCP analysis and discovered a unique polarity of cells in Xenopus gastrula epidermis and the neural plate. The proposed studies will use the new tools to address the following key questions that continue to challenge the field. A. What mechanisms are responsible for core PCP protein segregation in polarized cells? B. What are the spatial cues or signals that control PCP? C. How does cell polarization translate into morphogenetic cell behaviors? Our experiments will uncover molecular mechanisms regulating polarization of the core PCP protein Vangl2 to the anterior apical edge of cells in the Xenopus. Other studies will clarify the role of Wnt ligands in this process and identify new proteins that function in PCP using mass spectrometry-based approaches. These experiments will use Xenopus embryos, a unique in vivo model, in which biochemical, embryological and cell biological approaches can be combined. The proposed studies will advance the knowledge of basic cell biological mechanisms underlying vertebrate early morphogenetic events, such as gastrulation and neurulation. Since misregulation of Wnt and PCP signaling has been causally linked to many congenital defects and syndromes, polycystic kidney disease and multiple cancers, these studies are highly relevant to human health.