Signaling mechanisms Controlling Planar Cell Polarity

控制平面细胞极性的信号机制

• 批准号: 8838161
• 负责人: Jeffrey D. Axelrod
• 金额: $ 36.23万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8838161
• 关键词: Abdomen; Address; Anterior; Apical; Axon; Biological; Biological Models; Cells; Collaborations; Complex; Congenital Abnormality; Congenital Heart Defects; Core Protein; Data; Defect; Development; Distal; Drosophila genus; Dsh protein; Epithelial; Eye; Fatty acid glycerol esters; Foundations; Funding; Hair; Health; Joints; Leg; Link; Microtubule-Associated Proteins; Microtubules; Modeling; Molecular Motors; Motor; Neoplasm Metastasis; Neural Tube Closure; Physiological; Physiological Processes; Play; Polycystic Kidney Diseases; Production; Property; Protein Isoforms; Proteins; Recruitment Activity; Regulation; Role; Series; Side; Signal Transduction; Situs Inversus; Skin; Structure; Synapses; System; Tissues; Ubiquitination; Vertebrates; Vesicle; Wing; Work; Wound Healing; cancer cell; deafness; fascinate; fly; insight; interest; migration; molecular asymmetry; novel; planar cell polarity; polarized cell; research study; response; trafficking; transcytosis; ubiquitin-protein ligase

DESCRIPTION (provided by applicant): Planar Cell Polarity (PCP) signaling polarizes cells in epithelial sheets along an axis orthogonal to their apical- basal axis. Most of our mechanistic understanding of PCP signaling derives from work in Drosophila. However, a range of medically important developmental defects and physiological processes in vertebrates are under its control. PCP in vertebrates appears to conserve much or all of control of PCP signaling, including neural tube closure defects, polycystic kidneys, conotruncal heart defects, deafness and situs inversus. PCP polarizes skin and hair, and underlies directed migration during wound healing and invasion and metastasis of malignant cells the mechanism uncovered in flies, motivating considerable interest in studying PCP both in Drosophila. Studies in Drosophila reveal a modular system controlling PCP. A 'global' module comprising Fat(Ft), Dachsous(Ds) and Four-jointed(Fj) converts opposing tissue-level expression gradients of Fj and Ds into subcellular asymmetry of intercellular Ft-Ds heterodimers, and could therefore align PCP with the tissue axes. A 'core' module amplifies molecular asymmetry, localizing proximal (Van Gogh and Prickle) and distal (Frizzled, Dishevelled[Dsh]) proteins to opposite sides of the cell and coordinating polarity between neighboring cells. Morphological responses to the resulting molecular asymmetry are tissue specific. We have identified a mechanism linking these modules in series, and in so doing, revealed a fascinating cell biological mechanism. The global components Ft and Ds, via novel junctional ultrastructures, organize and tether arrays of polarized apical microtubules (MTs) that serve as substrates for directional trafficking of Dsh, thereby introducing a directional bias to the core module. Directional trafficking of Dsh breaks symmetry to bias core protein polarization. A paradox was the observation that the relationship between the direction of the global gradients and the direction of core module polarization is not conserved between tissues. We found that the predominance of the Prickle(Pk) or Spiny-legs(Sple) isoform of the core PCP component Pk controls gradient interpretation in these tissues by determining the direction of gradient dependent MTs, and thus the direction of MT dependent Dsh trafficking. These results raise a number of fascinating questions that we address in this proposal. How do the global components organize apical MTs? We hypothesize that Ft and Ds recruit proteins that capture and organize MTs. We will investigate how Pk-Sple controls Ft-Ds dependent MT orientation. Our data indicate that the Ft- Ds mechanism functions partially redundantly with a second signal originating at the wing margin. Preliminary data indicate that Wnt4 serves as this other signal, also by organizing polarized MTs. How does this other signal function? Once MTs are established, we wish to understand whether Dsh vesicle production is directly linked to these structures, and to study the signals for internalization and the control of molecular motors. Finally, we will study the E3 Ubiquitin ligase Cul1, which we have identified as a regulator of Pk function.

描述（由申请人提供）：平面细胞极性（PCP）信号传导使上皮层中的细胞沿与其顶-基底轴正交的轴沿着极化。我们对PCP信号传导机制的理解大多来自果蝇的研究。然而，脊椎动物的一系列医学上重要的发育缺陷和生理过程都在其控制之下。脊椎动物体内的五氯苯酚似乎保留了对五氯苯酚信号传导的大部分或全部控制，包括神经管闭合缺陷、多囊肾、圆锥动脉干心脏缺陷、耳聋和内脏逆位。PCP极化皮肤和毛发，并在伤口愈合和恶性细胞的侵袭和转移过程中的定向迁移的基础上，在苍蝇中发现的机制，激发了在果蝇中研究PCP的相当大的兴趣。对果蝇的研究揭示了控制五氯苯酚的模块系统。包括脂肪（Ft）、Dachsous（Ds）和四关节（Fj）的“全局”模块将Fj和Ds的相反组织水平表达梯度转化为细胞间Ft-Ds异二聚体的亚细胞不对称性，并且因此可以将PCP与组织轴对齐。一个“核心”模块放大了分子的不对称性，将近端（货车Gogh和Prickle）和远端（Frizzled，Dishevelled[Dsh]）蛋白定位到细胞的相对两侧，并协调相邻细胞之间的极性。由此产生的分子不对称性的形态学反应是组织特异性的。我们已经确定了一种将这些模块串联起来的机制，并在此过程中揭示了一种迷人的细胞生物学机制。全球组件Ft和Ds，通过新的交界超微结构，组织和拴系阵列的极化顶端微管（MT），作为基板的定向贩运DSH，从而引入了方向性的偏见的核心模块。Dsh的定向运输破坏对称性以偏置核心蛋白极化。一个悖论是观察到全局梯度的方向和核心模块极化的方向之间的关系在组织之间不守恒。我们发现，优势的刺（Pk）或刺腿（Sple）亚型的核心PCP组件Pk控制梯度解释这些组织通过确定梯度依赖MT的方向，从而MT依赖Dsh运输的方向。这些结果提出了一些有趣的问题，我们在这个建议中解决。全球组件如何组织顶端MT？我们假设，Ft和Ds招募蛋白质捕获和组织MT。我们将研究Pk-Sple如何控制Ft-Ds依赖的MT取向。我们的数据表明，Ft-Ds机制的功能部分冗余的第二个信号起源于机翼边缘。初步数据表明，Wnt 4也通过组织极化MT充当该另一信号。另一个信号是如何工作的？一旦MT被建立，我们希望了解Dsh囊泡的产生是否与这些结构直接相关，并研究内化的信号， 分子马达的控制最后，我们将研究E3泛素连接酶Cul 1，我们已经确定为Pk功能的调节器。