Planar Cell Polarity Signaling in Hair Follicle Formation

描述（由申请人提供）：

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.