PROJECT SUMMARY The evolutionarily conserved Sonic Hedgehog (SHH) signaling pathway governs tissue morphogenesis during development and contributes to tissue homeostasis in adults. Alteration of pathway activity drives developmental disorders including Holoprosencephaly (HPE), Pallister-Hall Syndrome and Basal Cell Nevus syndrome. Inappropriate activation of signaling post-developmentally is frequently associated with cancer, being causative in basal cell carcinoma and medulloblastoma, and implicated as a survival factor in a range of additional tumor types. As such, there is significant interest and therapeutic potential in defining the mechanisms governing SHH pathway activity. My laboratory’s long-term goal is to define the regulatory processes governing SHH pathway activity during development and use this knowledge to identify opportunities for targeting inappropriate SHH signaling in disease. Over the next 5 years, we will continue to work toward this goal by interrogating and defining the molecular mechanisms controlling pivotal regulatory steps of the SHH signal transduction cascade. We are focused on elucidating 1) how SHH ligand release and transport are controlled to establish a morphogen gradient, 2) how SMO activation is controlled and how it coordinates its activity with other G protein coupled receptors at the primary cilium, and 3) how GLI transcriptional activator induction and destabilization are coordinated to assure an appropriate transcriptional response.