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.
Cilia-planar polarity effectors (CPLANEs) are important components of both planar cell polarity and ciliogenesis, the disruption of which are associated with neural tube defects and ciliopathies. In this research proposal, we will determine how the CPLANE proteins form a molecular module to control skin development and skin cancer formation. Knowledge gained from this study will help us to understand the roles of the CPLANEs in polarity and cilia formation, and provide insight into disease mechanisms underlying neural tube defects, ciliopathies, and basal cell carcinoma.
|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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