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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
1R01AR061485-01
Application #
8163555
Study Section
Arthritis, Connective Tissue and Skin Study Section (ACTS)
Program Officer
Baker, Carl
Project Start
2011-07-11
Project End
2012-04-30
Budget Start
2011-07-11
Budget End
2012-04-30
Support Year
1
Fiscal Year
2011
Total Cost
$241,988
Indirect Cost
Name
University of Colorado Denver
Department
Dermatology
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
Yang, N; Leung, E L-H; Liu, C et al. (2017) INTU is essential for oncogenic Hh signaling through regulating primary cilia formation in basal cell carcinoma. Oncogene 36:4997-5005
Toriyama, Michinori; Lee, Chanjae; Taylor, S Paige et al. (2016) The ciliopathy-associated CPLANE proteins direct basal body recruitment of intraflagellar transport machinery. Nat Genet 48:648-56
Liu, Ying; Snedecor, Elizabeth R; Choi, Yeon Ja et al. (2016) Gorab Is Required for Dermal Condensate Cells to Respond to Hedgehog Signals during Hair Follicle Morphogenesis. J Invest Dermatol 136:378-86
Liu, Ying; Snedecor, Elizabeth R; Zhang, Xu et al. (2016) Correction of Hair Shaft Defects through Allele-Specific Silencing of Mutant Krt75. J Invest Dermatol 136:45-51
Snedecor, Elizabeth R; Sung, Clifford C; Moncayo, Alejandra et al. (2015) Loss of primary cilia in melanoma cells is likely independent of proliferation and cell cycle progression. J Invest Dermatol 135:1456-1458
Yang, Ning; Li, Li; Eguether, Thibaut et al. (2015) Intraflagellar transport 27 is essential for hedgehog signaling but dispensable for ciliogenesis during hair follicle morphogenesis. Development 142:2194-202
Chen, Jiang; Laclef, Christine; Moncayo, Alejandra et al. (2015) The ciliopathy gene Rpgrip1l is essential for hair follicle development. J Invest Dermatol 135:701-709
Liu, Ying; Snedecor, Elizabeth R; Zhang, Xu et al. (2015) Correction of Hair Shaft Defects through Allele-Specific Silencing of Mutant Krt75. J Invest Dermatol :
Dai, D; Li, L; Huebner, A et al. (2013) Planar cell polarity effector gene Intu regulates cell fate-specific differentiation of keratinocytes through the primary cilia. Cell Death Differ 20:130-8
Yasuda, Masahito; Claypool, David J; Guevara, Erika et al. (2013) Genetic manipulation of keratinocyte stem cells with lentiviral vectors. Methods Mol Biol 989:143-51

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