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

项目总结 FUZ、INTU和WDPCP是组织特有的平面细胞极性(PCP)信号效应器，在两者中都有作用 PCP和纤毛的形成。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动态平衡中发挥重要作用 与神经管缺陷和纤毛疾病有关。在哺乳动物的皮肤中，五氯苯酚是毛发所必需的。 图案化。最初的纤毛对于刺猬通路--一种分子信号机制--是必不可少的。 对毛囊形态发生和基底细胞癌的发展至关重要。据信， CPLANE在细胞水平上调节由核心PCP组分建立的极性线索。在纤毛发生过程中， CPLANE促进鞭毛内运输蛋白的运输。然而，精确的分子 机制尚不清楚。在这项研究中，我们将研究CPLANEs在皮肤中的功能 形态发生和动态平衡。首先，我们将确定Wdpcp基因是否与PCP和/或 纤毛在小鼠皮肤中的发生，以及CPLANE基因是否在皮肤中参与PCP的冗余 通过同时扰乱Wdpcp和Intu基因来实现。随后，我们将研究 从功能丧失和致病机制研究CPLANE蛋白的分子功能 突变会损害纤毛的形成。最后，我们将确定致癌基因突变是否对 激活的Hedgehog信号和基底细胞癌的形成，可以促进原发纤毛的形成 通过抑制纤毛分解机制或上调纤毛生成基因的转录，包括 对CPLANE进行编码的那些。了解CPLANEs的分子功能将提供重要的 深入了解毛囊构型、基底细胞癌形成、神经的分子机制 管子缺陷和纤毛病变。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 还将深入了解致癌的HH突变如何重新编程角质形成细胞中的纤毛形成过程， 从而为皮肤保护和肿瘤预防的新机制提供了新的思路。

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.