Molecular functions of cilia-planar polarity effectors (CPLANEs) in skin morphogenesis and homeostasis

纤毛平面极性效应器（CPLANE）在皮肤形态发生和稳态中的分子功能

• 批准号: 9816843
• 负责人: Jiang Chen
• 金额: $ 27.15万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-11 至 2022-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9816843
• 关键词: Affect; Basal cell carcinoma; Biological; Carrier Proteins; Cilia; Complex; Core Protein; Cues; Development; Disease; Embryo; Erinaceidae; Event; Fibroblasts; Genes; Genetic Transcription; Hair; Hair follicle structure; Homeostasis; Human; Impairment; Investigation; Knowledge; Light; Link; Malignant Epithelial Cell; Mammalian Cell; Mediating; Molecular; Morphogenesis; Mus; Mutation; Neural Tube Defects; Oncogenic; Pathogenicity; Pathway interactions; Patients; Pattern; Peripheral; Prevention; Process; Proteins; Research Proposals; Role; Signal Transduction; Skin; Skin Cancer; Specimen; Tissues; Transcript; ciliopathy; cilium biogenesis; insight; keratinocyte; kinetosome; loss of function; novel; planar cell polarity; postnatal; programs; protein function; protein transport; skin morphogenesis; skin organogenesis; smoothened signaling pathway; trafficking; tumor; tumorigenesis

PROJECT SUMMARY FUZ, INTU, and WDPCP are tissue-specific planar cell polarity (PCP) signaling effectors, and function in both PCP and cilia formation. These PCP effectors are now collectively called cilia-planar polarity effectors (CPLANEs). PCP and cilia perform important functions during tissue morphogenesis and homeostasis, and are linked to neural tube defects and ciliopathies. In the mammalian skin, PCP is known to be essential for hair patterning. The primarily cilium is essential for the hedgehog pathway – a molecular signaling mechanism critical for hair follicle morphogenesis and the development of basal cell carcinoma. It is believed that CPLANEs mediate the polarity cues set up by the core PCP components at the cellular level. In ciliogenesis, CPLANEs facilitate the trafficking of intraflagellar transport proteins. However, the precise molecular mechanism remains unclear. In this investigation, we will examine the functions of the CPLANEs in skin morphogenesis and homeostasis. First, we will determine whether the Wdpcp gene is involved in PCP and/or ciliogenesis in the mouse skin, and whether the CPLANE genes participate in PCP in the skin in a redundant manner by simultaneously disrupting the Wdpcp and the Intu genes. Subsequently, we will examine the molecular functions of the CPLANE proteins by investigating how loss-of-function and pathogenic CPLANE mutations impair ciliogenesis. Finally, we will determine whether oncogenic mutations, responsible for activated hedgehog signaling and basal cell carcinoma formation, could promote the formation of primary cilia by inhibiting the cilia disassembly mechanism or by upregulating the transcription of ciliogenic genes, including those encoding the CPLANEs. Understanding the molecular functions of CPLANEs will provide important insight into the molecular mechanisms underlying hair follicle patterning, basal cell carcinoma formation, neural tube defects, and ciliopathies. In the long-run, knowledge gained from this investigation will provide important insight into how the CPLANE proteins orchestrate or segregate PCP and ciliogenesis in the mammalian skin. It will also provide insight into how oncogenic Hh mutations reprogram the ciliogenic processes in keratinocytes, thereby, shed light on novel mechanism of skin protection and tumor prevention.

项目摘要 FUZ、INTU和WDPCP是组织特异性平面细胞极性（PCP）信号效应子，在两种细胞中均起作用。 五氯苯酚和纤毛形成。这些PCP效应器现在统称为纤毛平面极性效应器 （CPLANEs）. PCP和纤毛在组织形态发生和体内平衡过程中发挥重要作用， 与神经管缺陷和纤毛病有关在哺乳动物的皮肤中，五氯苯酚对毛发至关重要 模式化主要纤毛是必需的刺猬途径-一种分子信号机制 对于毛囊形态发生和基底细胞癌的发展至关重要。据信 CPLANEs在细胞水平上介导PCP核心成分建立的极性线索。在纤毛发生中， CPLANE促进鞭毛内转运蛋白的运输。然而，精确的分子 机制尚不清楚。在本研究中，我们将研究皮肤中CPLANEs的功能 形态发生和体内平衡。首先，我们将确定Wdpcp基因是否参与PCP和/或 小鼠皮肤纤毛发生，以及CPLANE基因是否参与PCP在皮肤中的冗余表达， 通过同时破坏Wdpcp和Intu基因的方式。随后，我们将研究 通过研究功能丧失和致病性CPLANE如何影响CPLANE蛋白的分子功能， 突变损害纤毛发生。最后，我们将确定是否致癌突变，负责 激活hedgehog信号和基底细胞癌形成，可促进初级纤毛的形成 通过抑制纤毛分解机制或通过上调生毛基因的转录，包括 那些编码CPLANE的。了解CPLANE的分子功能将提供重要的 深入了解毛囊模式化、基底细胞癌形成、神经系统疾病、 管缺陷和纤毛病变。从长远来看，从这次调查中获得的知识将提供重要的 深入了解CPLANE蛋白如何协调或分离哺乳动物皮肤中的PCP和纤毛发生。它 也将提供深入了解致癌Hh突变如何重新编程角质形成细胞中的纤毛生成过程， 从而揭示了皮肤保护和肿瘤预防的新机制。