Planar cell polarity mechanisms and systems architecture

平面细胞极性机制和系统架构

• 批准号: 10018920
• 负责人: Jeffrey D. Axelrod
• 金额: $ 97.94万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-16 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10018920
• 关键词: Adult; Ataxia; Biological; Biological Models; Cell division; Cells; Cellular Structures; Defect; Development; Disease; Drosophila genus; Ependyma; Epilepsy; Epithelial; Epithelium; Event; Eye; Genes; Hair; Human; Knowledge; Medical; Modeling; Molecular; Mus; Mutate; Mutation; Neoplasm Metastasis; Neural Tube Defects; Neuronal Migration Disorder; Pathology; Pathway interactions; Phenotype; Physiological Processes; Polycystic Kidney Diseases; Process; Signal Transduction; Situs Inversus; Skin; Syndrome; Therapeutic Intervention; Tissues; Vertebrates; Work; cancer cell; cell behavior; cell motility; conotruncal heart defect; deafness; fly; interest; migration; mutant; paralogous gene; planar cell polarity; polarized cell; system architecture; wound healing

Summary/Abstract Planar cell polarity (PCP) signaling controls the polarization of cells within the plane of an epithelium, orienting asymmetric cellular structures, cell divisions and cell migration and is well conserved from Drosophila to vertebrates. Most of our mechanistic understanding of PCP signaling has and will likely continue to derive from work using Drosophila as a model system. In flies, PCP signaling controls the orientation of hairs on the adult cuticle, chirality and orientation of ommatidia in the eye, orientation of cell divisions, and related processes in other tissues. While much of our focus is on mechanistic studies in flies, numerous medically important developmental defects and physiological processes in vertebrates are also under control of PCP signaling, motivating considerable interest in studying PCP both in Drosophila and in vertebrate model systems. In vertebrates, defects in the core PCP mechanism result in a range of developmental anomalies and diseases including open neural tube defects, conotruncal heart defects, deafness and situs inversus and heterotaxy, and has been (incorrectly) implicated in polycystic kidney diseases. PCP is also believed to underlie the directed migration of malignant cells during invasion and metastasis and during wound healing. PCP polarizes skin and hair and the ependyma. The PCP component Prickle, though perhaps not involving the PCP pathway, is mutated in an epilepsy-ataxia syndrome. Mutations in `global' PCP components have recently been associated with a human disorder of neuronal migration and proliferation. These phenotypes can be studied in vertebrate models of PCP gene mutants, and provide excellent opportunities to understand vertebrate PCP signaling and its morphogenetic manifestations. Cellular behaviors controlled by PCP in vertebrates vary, and the expanded numbers of paralogs for the PCP genes in mouse compared to flies suggests the possibility of functional diversification. Hence there is a strong need to understand how PCP signaling is adapted in these various contexts. This proposal aims to dissect the molecular and cell biological mechanisms of PCP signaling using Drosophila as a model system and to extend our understanding to selected vertebrate PCP signaling events. The proposed work will both enhance our knowledge of fundamental mechanisms as well as lay the groundwork for potential therapeutic interventions for PCP related pathologies.

总结/摘要 平面细胞极性（PCP）信号传导控制上皮平面内细胞的极化， 定向不对称的细胞结构、细胞分裂和细胞迁移，并且在细胞结构、细胞分裂和细胞迁移中很好地保守 从果蝇到脊椎动物我们对PCP信号传导的大多数机械理解已经并将 很可能继续从以果蝇为模型系统的工作中获得。在苍蝇中，PCP信号 控制成人角质层上毛发的方向、眼睛中小眼的手性和方向， 细胞分裂的方向以及其他组织中的相关过程。 虽然我们的重点是苍蝇的机制研究，许多医学上重要的 脊椎动物的发育缺陷和生理过程也受到五氯苯酚的控制 信号，激发了人们对果蝇和脊椎动物中PCP研究的极大兴趣 模型系统在脊椎动物中，PCP核心机制的缺陷导致一系列的 发育异常和疾病，包括开放性神经管缺陷、圆锥干心脏 缺陷，耳聋和内脏逆位和异位，并已（错误地）牵连在 多囊肾病PCP也被认为是恶性细胞定向迁移的基础 在侵袭和转移期间以及在伤口愈合期间。五氯苯酚使皮肤和头发极化， 室管膜。五氯苯酚的成分Prickle，虽然可能不涉及五氯苯酚途径，但发生了突变 癫痫-共济失调综合征“全球”五氯苯酚成分的突变最近被 与人类神经元迁移和增殖障碍相关。这些表型可以是 在脊椎动物模型中研究PCP基因突变体，并提供了极好的机会， 了解脊椎动物PCP信号传导及其形态发生表现。细胞行为 在脊椎动物中，五氯苯酚控制的基因数量各不相同， 小鼠与苍蝇相比表明功能多样化的可能性。因此，有一个强大的 我们需要了解PCP信令如何适应这些不同的环境。 该建议旨在使用以下方法剖析PCP信号传导的分子和细胞生物学机制： 果蝇作为模式系统，并将我们的理解扩展到选定的脊椎动物PCP 信号事件。所提议的工作既将增进我们对基本机制的了解， 并为五氯苯酚相关病症的潜在治疗干预奠定基础。