The Role of Hedgehog-Gli Pathway Regulators in Skin Development and Tumorigenesis

Proper control of Hedgehog (Hh) signaling is critical for hair follicle morphogenesis and ectopic Hh pathway activity is a hallmark of basal cell carcinoma (BCC), the most common type of skin cancer. Mutations in Hh pathway components such as the Hh-binding receptor PATCHED1 (PTCH1) are frequently found in BCC. However, how Hh pathway activation disrupts normal skin homeostasis to promote BCC formation remains poorly understood. Gli2, the major mediator of Hh signaling is essential for hair follicle development and its overexpression in the epidermis induces BCC formation. Despite the importance of Gli2 in the skin, how it is regulated during skin development and tumorigenesis is unclear. Using a genetic approach with loss-of-function mouse mutants and primary keratinocyte cultures, I have uncovered the distinct and overlapping functions of Sufu and Kif7, two evolutionarily conserved regulators of the Hh pathway, during skin development and tumorigenesis. Sufu and Kif7 play opposing roles in Hh signaling through the regulation of Gli2 subcellular distribution, and Kif7 performs distinct Sufu-dependent and –independent functions. In addition, deletion of both Sufu and Kif7 in embryonic skin leads to complete loss of follicular fate and compromised epidermal differentiation. In the adult skin, inactivation of Sufu does not drive BCC formation and requires additional genetic alterations such as the loss of Kif7. Using a Ptc1 mouse model for BCC, I have identified previously unrecognized molecular pathways and cellular events involved in BCC pathogenesis. This includes, aberrant cell cycle progression, loss of cell cycle checkpoint regulation, and suppression of the p53 response. Overall my work provides critical insight into the molecular control of Hh signaling and the downstream events driving BCC formation.Ph