Planar Cell Polarity Signaling in Hair Follicle Formation

描述（由申请人提供）： 平面细胞极性（PCP）信号通路，又称非经典Wnt信号通路（Wnt/PCP），是一种进化上保守的信号通路。在果蝇中建立的许多概念可以在包括人类在内的脊椎动物中找到。PCP信号在细胞和亚细胞水平上对上皮极化起着重要作用。PCP信号通路的中断可导致人类疾病，如神经管缺陷（NTD），这是最常见的出生缺陷形式之一。最近的研究还表明，PCP信号传导与皮肤附属物毛囊的发育有关。具体而言，已显示该信号传导途径的核心PCP基因控制毛囊的方向，而组织特异性PCP效应基因控制毛囊分化。这些研究不仅为PCP信号通路是调控毛囊形成的重要分子信号机制提供了有力的证据，而且证明了毛囊可以作为研究PCP信号通路的新模型。使用毛囊作为模型来研究PCP信号传导的概念进一步得到以下观察结果的支持：组织特异性PCP效应基因也是初级纤毛形成所必需的，初级纤毛是处理音刺猬（Shh）信号所必需的细胞器。事实上，初级纤毛和Shh信号不仅对毛囊的发育很重要，它们还与基底细胞癌（BCC）的发展有关。本项目的重点是剖析五氯苯酚信号通路在哺乳动物皮肤中的功能。由于PCP信号通路通过调节微管和肌动蛋白微丝细胞骨架网络来控制无脊椎动物和脊椎动物的细胞功能，这些网络对于初级纤毛的形成和功能也是必不可少的，因此我们假设，在小鼠中，PCP信号通路通过调节初级纤毛形成和功能期间的细胞骨架系统来控制毛囊的形成。我们建议使用PCP基因的功能丧失突变小鼠模型来验证这一假设。在具体目标1中，我们将确定PCP信号通路的组织特异性PCP效应基因是否通过在初级纤毛形成期间调节微管细胞骨架来控制毛囊分化。在具体目标2中，我们将确定PCP信号通路的核心PCP基因是否通过调节角质形成细胞中初级纤毛极化过程中的肌动蛋白细胞骨架系统来控制毛囊方向。在具体目标3中，我们将通过检查表皮角质形成细胞中核心PCP和组织特异性PCP效应基因之间的潜在遗传和分子相互作用来确定PCP信号通路的遗传层次。这些研究将确定毛囊形成过程中PCP信号通路的分子和细胞功能，并可能为头发和其他皮肤疾病（如脱发和BCC）的发展提供新的见解，并可能为这些皮肤疾病开发新的治疗策略。

DESCRIPTION (provided by applicant): The planar cell polarity (PCP) signaling, or non-canonical Wnt (Wnt/PCP) signaling, is an evolutionarily conserved signaling pathway. Many concepts established in Drosophila can be found in vertebrate animals including man. PCP signaling plays an essential role in polarizing the epithelium at cellular and subcellular levels. Disruption of the PCP signaling pathway can result in human diseases such as neural tube defects (NTDs), one of the most common forms of birth defects. Recent studies have also implicated PCP signaling in the development of a skin appendage, the hair follicle. Specifically, core PCP genes of this signaling pathway have been shown to control the orientation of the hair follicles, whereas tissue-specific PCP effector genes control hair follicle differentiation. These studies not only provide strong evidence that the PCP signaling pathway is an important molecular signaling mechanism in regulating the formation of hair follicle, they also demonstrate that the hair follicle can be used as a novel model to understand PCP signaling in mammals. The concept of using the hair follicle as a model to investigate PCP signaling is further supported by the observation that the tissue-specific PCP effector genes are also required for the formation of primary cilia, cellular organelles that are essential for processing the sonic hedgehog (Shh) signals. In fact, primary cilia and Shh signaling are not only important for the development of the hair follicle, they are also implicated in the development of basal cell carcinoma (BCC). The focus of this project is to dissect the functions of the PCP signaling pathway in the mammalian skin. Because the PCP signaling pathway controls cellular functions of invertebrate and vertebrate animals by regulating the microtubule and actin microfilament cytoskeleton networks, which are also essential for primary cilia formation and function, we hypothesize that, in mice, the PCP signaling pathway controls hair follicle formation by regulating the cytoskeleton system during primary cilia formation and function. We propose to use loss-of-function mutant mouse models of PCP genes to test this hypothesis. In Specific Aim 1, we will determine if tissue-specific PCP effector genes of the PCP signaling pathway control hair follicle differentiation by regulating the microtubule cytoskeleton during primary cilia formation. In Specific Aim 2, we will determine if the core PCP genes of the PCP signaling pathway control hair follicle orientation by regulating the actin cytoskeleton system during primary cilia polarization in keratinocytes. In Specific Aim 3, we will determine the genetic hierarchy of the PCP signaling pathway by examining potential genetic and molecular interactions between core PCP and tissue-specific PCP effector genes in epidermal keratinocytes. These studies will determine the molecular and cellular functions of the PCP signaling pathway during hair follicle formation, and may provide new insights into the development of hair and other skin diseases such as alopecia and BCC, based on which novel treatment strategies for these skin conditions may be developed.