Planar cell polarity mechanisms and systems architecture

摘要/摘要 平面细胞极性(PCP)信号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，并从 从果蝇到脊椎动物。我们对PCP信号的大部分机械性理解已经并将会 可能会继续使用果蝇作为模型系统的工作派生。在果蝇中，PCP信号 控制成人角质层上毛发的方向、眼内小眼的手性和方位， 细胞分裂的方向，以及其他组织中的相关过程。 虽然我们的大部分注意力都集中在苍蝇的机制研究上，但许多医学上重要的 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，激发了对果蝇和脊椎动物PCP研究的浓厚兴趣 模型系统。在脊椎动物中，核心PCP机制的缺陷导致一系列 发育异常和疾病，包括开放的神经管缺陷、圆锥干心脏 缺陷、耳聋、内翻和异位，并被(错误地)牵涉到 多囊肾病。PCP也被认为是恶性细胞定向迁移的基础 在侵袭和转移以及伤口愈合过程中。五氯苯酚使皮肤和头发极化， 室管膜。PCP组分的刺痛虽然可能不涉及PCP途径，但却发生了突变 患有癫痫-共济失调综合征。最近，全球PCP成分的突变 与人类神经元迁移和增殖障碍有关。这些表型可以是 在脊椎动物模型中研究PCP基因突变，并提供了极好的机会 了解脊椎动物PCP信号及其形态发生的表现。细胞行为 在脊椎动物中受PCP控制的情况各不相同，并且PCP基因在 与苍蝇相比，老鼠暗示了功能多样化的可能性。因此有一个很强的 需要了解PCP信令如何适应这些不同的环境。 这项建议旨在剖析PCP信号转导的分子和细胞生物学机制 以果蝇为模式系统，并将我们的理解扩展到选定的脊椎动物PCP 信号事件。拟议的工作既将增强我们对基本机制的知识 并为PCP相关病理的潜在治疗干预奠定了基础。

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.