Comparative analysis of PCP signaling architecture

描述（由申请人提供）：平面细胞极性（PCP）系统使一些上皮层中的细胞沿与其顶基轴正交的轴沿着极化，并且是许多生理功能所必需的。对果蝇（Drosophila）的研究产生了控制五氯苯酚的模块系统概念。五氯苯酚基因可以组合成功能模块，每个模块代表一个遗传和生化相关单位。然而，已经提出了描述主要（“全局”、“核心”和“效应器”）PCP模块之间的关系的冲突模型，表明各种组织特异性效应器模块上游的串联或并联关系。值得注意的是，PCP模块之间以及PCP模块与其目标之间的连接性存在争议。PCP信号传导的目标可能是在单细胞内起作用以构建极化结构的离散系统，或者可能是本身构成模块的多细胞单位，其中细胞内和细胞间的信号有助于图案化。PCP信号系统的组成部分，以及与它们相互作用的效应器系统，共同发挥作用，产生紧急模式。在特定细胞群中操纵单个PCP信号分子不仅在亚细胞水平上扰乱靶细胞的极化，而且在多细胞水平上扰乱极性模式，通常以特征性方式影响附近细胞。原则上，这类实验可以让我们推断出支配控制系统的结构，但分子相互作用和组织水平模式之间的关系非常复杂，无法直观理解。数学建模是解决这一问题的重要工具。在这里，我们建议结合联合收割机新的，混合模型，服从分析，与生物实验，以更好地了解PCP信号网络架构，以及是否一个或多个架构在不同的情况下的功能。具体来说，我们建议首先探测两个组织，翅膀和腹部，其中输出是头发极化，但其中互斥的模型架构已被提出的全球和核心模块和网络架构。接下来，我们将探讨第三个系统中的相应模块和网络架构，即刚毛，其中效应器是一个更复杂的多细胞系统，可能在如何响应PCP输入方面更加多样化。我们相信，这项工作将有助于加深对五氯苯酚的了解，这对于了解五氯苯酚导致的许多脊椎动物发育缺陷和疾病至关重要。这项工作还将产生广泛适用的数学工具以及可以与现有发展模型相结合的数学模型组件。

DESCRIPTION (provided by applicant): The Planar Cell Polarity (PCP) system polarizes cells in some epithelial sheets along an axis orthogonal to their apical-basal axis, and is necessary for numerous physiological functions. Studies in the fruit fly, Drosophila, have led to the concept of a modular system controlling PCP. The PCP genes can be grouped together into functional modules, each representing a genetically and biochemically related unit. However, conflicting models describing the relationships between the principal ("global," "core" and "effector") PCP modules have been proposed, suggesting either a series or parallel relationship upstream of the various tissue specific effector modules. Notably, the connectivity between the PCP modules, and between the PCP modules and their targets is controversial. Targets of PCP signaling may be discrete systems that act within single cells to build polarized structures, or may be multicellular units that themselves constitute modules in which signals within and between cells contribute to patterning. The components of the PCP signaling system, and the effector systems with which they interact, function together to produce emergent patterns. Manipulation of individual PCP signaling molecules in specified groups of cells not only perturbs the polarization of the targeted cells at a subcellular level, but also perturbs patterns of polarity at the multicellular level, often affecting nearby cells in characteristic ways. These kinds of experiments should, in principle, allow us to infer the architecture of the governing control systems, but the relationships between molecular interactions and tissue-level pattern are sufficiently complex that they defy intuitive understanding. Mathematical modeling has been an important tool to address this problem. Here, we propose to combine novel, hybrid models, amenable to analysis, with biological experimentation to better understand the PCP signaling network architecture and whether a single or multiple architectures function in different contexts. Specifically, we propose to first probe the global and core modules and network architecture in two tissues, wing and abdomen, in which the output is hair polarization, but in which mutually exclusive model architectures have been proposed. Next, we will probe the corresponding modules and network architecture in a third system, the bristles, in which the effector is a more complex multicellular system that may be more divergent in how it responds to PCP input. We believe that this work will result in an enhanced understanding of PCP, which will be important in understanding the many vertebrate developmental defects and diseases to which PCP contributes. The work will also produce broadly applicable mathematical tools as well as mathematical model components that can be integrated with existing developmental models.