Regulation of cell polarity by Wnt signaling

Wnt 信号传导调节细胞极性

• 批准号: 10224885
• 负责人: Sergei Sokol
• 金额: $ 46.85万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10224885
• 关键词: Address; Anterior; Antibodies; Apical; Biochemical; Biological; Birth; Cell Polarity; Cells; Congenital Abnormality; Cues; Disease; Disseminated Malignant Neoplasm; Embryo; Embryonic Development; Epidermis; Epithelial; Epithelial Cells; Event; Gastrula; Health; Human; Knowledge; Laboratories; Ligands; Link; Malignant Neoplasms; Mass Spectrum Analysis; Mediating; Metastatic to; Modeling; Molecular; Polycystic Kidney Diseases; Prevention; Process; Proteins; Regulation; Role; Side; Signal Transduction; Syndrome; System; Tissues; Translating; WNT Signaling Pathway; Wnt proteins; Xenopus; base; cell behavior; cell motility; experimental study; gastrulation; in vivo Model; interest; molecular marker; neural plate; planar cell polarity; polarized cell; protein function; segregation; sensor; tool; vertebrate embryos

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.

该建议涉及调节上皮细胞取向的信号传导机制 脊椎动物胚胎中的平面称为平面细胞极性（PCP）。这个常见 现象是由一组保守的蛋白质介导的，这些蛋白质极化 组织中的上皮细胞。分泌的Wnt蛋白已与控制有关 pcp的，但是Wnt蛋白是否以及如何为PCP提供方向输入 系统尚不清楚。我们的实验室对Wnt信号和 细胞极性，但由于缺乏可拖动模型和 合适的分子标记。最近，我们的小组开发了特定的抗体， 用于PCP分析的荧光传感器，发现细胞的独特极性 爪蟾表皮和神经板。拟议的研究将使用新的 解决继续挑战该领域的以下关键问题的工具。答：什么 机制负责极化细胞中的核心PCP蛋白分离？ B 控制PCP的空间提示或信号是什么？ C.细胞极化如何 转化为形态发生的细胞行为？我们的实验将发现分子 调节核心PCP蛋白VANGL2极化为前根尖的机制 爪蟾中细胞的边缘。其他研究将阐明Wnt配体在此中的作用 处理并使用基于质谱的新蛋白在PCP中起作用的新蛋白质 方法。这些实验将使用Xenopus Embryos，这是一种独特的体内模型， 可以组合哪种生化，胚胎和细胞生物学方法。这 拟议的研究将提高基本细胞生物学机制的知识 潜在的脊椎动物早期形态发生事件，例如胃和神经化。 由于Wnt和PCP信号的正调已与许多人有因果关系 先天性缺陷和综合征，多囊性肾脏疾病和多种癌症， 这些研究与人类健康高度相关。