Comparative analysis of PCP signaling architecture

描述（由申请人提供）：平面细胞极性（PCP）系统使一些上皮片上的细胞沿与其顶基轴正交的轴极化，这是许多生理功能所必需的。对果蝇的研究已经导致了控制PCP的模块化系统的概念。PCP基因可以组合成功能模块，每个模块代表一个遗传和生物化学相关的单元。然而，描述主要PCP模块（“全局”、“核心”和“效应器”）之间关系的相互矛盾的模型已经被提出，表明在各种组织特异性效应器模块的上游存在串联或平行关系。值得注意的是，PCP模块之间以及PCP模块与其目标之间的连通性是有争议的。PCP信号传导的目标可能是在单个细胞内形成极化结构的离散系统，也可能是多细胞单位，它们本身构成模块，其中细胞内和细胞间的信号有助于形成模式。PCP信号系统的组成部分，以及与它们相互作用的效应系统，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目标细胞的极化，而且在多细胞水平上扰乱极性模式，通常以特有的方式影响附近的细胞。原则上，这类实验应该允许我们推断出控制系统的结构，但分子相互作用和组织水平模式之间的关系非常复杂，难以直观理解。数学建模是解决这个问题的重要工具。在此，我们建议将易于分析的新型混合模型与生物实验相结合，以更好地了解PCP信号网络架构以及单一或多个架构在不同环境下的功能。具体而言，我们建议首先探索翅膀和腹部两个组织的全局和核心模块和网络架构，其中输出是毛发极化，但已经提出了互斥的模型架构。接下来，我们将探讨第三个系统中相应的模块和网络架构，即猪鬃，其中的效应器是一个更复杂的多细胞系统，在如何响应PCP输入方面可能会更加分散。我们相信这项工作将有助于增进对PCP的了解，这对于理解PCP导致的许多脊椎动物发育缺陷和疾病将是重要的。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成部分。

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.