PROJECT SUMMARY 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.