Planar cell polarity signaling in hair follicle formation

描述(由申请人提供)： 平面细胞极性(PCP)信号或非规范Wnt(Wnt/PCP)信号是一种进化保守的信号通路。在果蝇中建立的许多概念在包括人类在内的脊椎动物中都可以找到。PCP信号在细胞和亚细胞水平上的上皮极化中起着重要作用。PCP信号通路的中断可能导致人类疾病，如神经管缺陷(NTDS)，这是最常见的出生缺陷形式之一。最近的研究还表明，PCP信号与皮肤附属物毛囊的发育有关。具体地说，该信号通路的核心PCP基因被证明控制毛囊的方向，而组织特异性PCP效应基因控制毛囊的分化。这些研究不仅提供了强有力的证据，表明PCP信号通路是调控毛囊形成的重要分子信号机制，也表明毛囊可以作为一种新的模型来理解哺乳动物的PCP信号。利用毛囊作为模型来研究PCP信号的概念进一步得到了组织特异性PCP效应基因也是形成初级纤毛所必需的观察的支持，初级纤毛是处理声波刺激性(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，而且与基底细胞癌(BCC)的发生有关。本项目的重点是剖析PCP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，这两个网络对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过程中的细胞骨架系统来控制毛囊的形成。我们建议使用功能丧失的PCP基因突变小鼠模型来验证这一假设。在特定的目标1中，我们将确定PCP信号通路中的组织特异性PCP效应基因是否通过调节初级纤毛形成过程中的微管细胞骨架来控制毛囊分化。在特定的目标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的定向。在具体目标3中，我们将通过检测表皮角质形成细胞中核心PCP和组织特异性PCP效应基因之间潜在的遗传和分子相互作用来确定PCP信号通路的遗传等级。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，并可能为毛发和其他皮肤病(如脱发和基底细胞癌)的发展提供新的见解，从而为这些皮肤病开发新的治疗策略。 公共卫生相关性： 平面细胞极性(PCP)信号是上皮组织正常功能的重要分子调控机制。这项拟议的研究旨在利用毛囊--皮肤的一个附属物--作为模型，研究PCP信号如何控制哺乳动物的细胞功能。了解PCP信号通路将有助于我们寻找治疗PCP相关疾病的新机会。

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. PUBLIC HEALTH RELEVANCE: Planar cell polarity (PCP) signaling is an important molecular control mechanism for proper functions of epithelial tissues. The proposed study is aimed at using the hair follicle, an appendage of the skin, as a model to investigate how PCP signaling control cellular functions in mammals. Understanding the PCP signaling pathway will help us to identify novel therapeutic opportunities for PCP related diseases.