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定向的信号传导机制， 在脊椎动物胚胎中的平面，被称为平面细胞极性（PCP）。这一共同 这种现象是由一组保守的蛋白质介导的，这些蛋白质位于蛋白质的一侧。 组织中的上皮细胞分泌的Wnt蛋白与对照组有牵连。 但是Wnt蛋白是否以及如何为PCP提供方向性输入， 系统仍然不清楚。我们的实验室对Wnt信号传导有着长期的兴趣， 细胞极性，但机制研究受到缺乏易于处理的模型的阻碍， 合适的分子标记。最近，我们小组已经开发出特异性抗体， 用于PCP分析的荧光传感器，并发现了细胞的独特极性， 爪蟾原肠胚表皮和神经板。拟议的研究将使用新的 这些工具可用于解决该领域继续面临的以下关键问题。A.什么 机制负责核心PCP蛋白分离极化细胞？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的行为我们的实验将揭示分子 调节PCP核心蛋白Vangl 2向前顶极化的机制 非洲爪蟾细胞的边缘其他研究将阐明Wnt配体在这一过程中的作用。 使用基于质谱的方法处理和鉴定在PCP中起作用的新蛋白质 接近。这些实验将使用非洲爪蟾胚胎，一种独特的体内模型， 其中生物化学、胚胎学和细胞生物学方法可以结合。的 拟议的研究将推进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，如原肠胚和神经胚。 由于Wnt和PCP信号的错误调节与许多疾病的发生有因果关系， 先天性缺陷和综合征，多囊肾病和多种癌症， 这些研究与人类健康密切相关。