Hedgehog, Patched, and Gli in Medulloblastoma

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DESCRIPTION (provided by applicant): Brain tumors are the number one cause of cancer death in children and medulloblastoma is the most common malignant brain tumor. The signaling pathway involving the secreted factor Sonic Hedgehog (Shh) and the downstream genes Patched (Ptc) and Gli play critical roles in brain development, particularly that of the cerebellum. Shh, released by Purkinje cells, relieves Ptc-mediated repression of cell growth and promotes proliferation of granule cell precursors. Granule cells undergo proliferation in the external granule layer (EGL) of the cerebellum during development, then exit the cell cycle and migrate inwardly along radial glia fibers to the internal granule layer (IGL). Medulloblastoma is thought to arise from a granule cell precursor. Recent studies have demonstrated that mutations in components of the Shh pathway are associated with medulloblastoma in humans. Furthermore, approximately 15% of mice heterozygous for a Ptc mutation develop medulloblastoma at 6-12 months of age. We have shown that mis-expression of Shh in the mouse embryonic and postnatal cerebellum produces tumors. Our overall aim is to explore the mechanism by which activation of the Sonic Hedgehog pathway leads to medulloblastoma formation. We will further develop and characterize a mouse model of medulloblastoma in which Shh is mis-expressed in the embryonic cerebellum using a retroviral vector introduced into the embryonic brain by ultrasound-guided injection. The involvement of Ptc, and Gli1 will be determined by the following approaches: 1) we will characterize how activation of the Shh-signaling pathway maintains some early EGL granule neurons in a proliferative, undifferentiated state and induces medulloblastoma formation in wild type mice, 2) we will test whether activation of the Shh-signaling pathway in mice heterozygous for a null mutation in Ptc results in a synergistic effect, with accelerated and/or a higher frequency of tumorigenesis, and 3) we will test whether Gli1 is required downstream of Shh for tumor formation and whether heterozygosity for Gli3 enhances tumor formation by injecting Shh-retrovirus into Gli1-/- and Gli3+/- mutants. This system provides a unique opportunity to investigate an in vivo animal model of childhood medulloblastoma, and to determine the roles of Ptc and Gli in tumorigenesis.