Medulloblastoma, the most common pediatric malignant tumor, arises from the granule cell precursors (GCPs) in the cerebellum. Sonic hedgehog (Shh)/Patched signaling tightly regulates the proliferation of the GCPs during development. Deregulation of this pathway results in uncontrolled growth and subsequent medulloblastoma formation in both humans and mice. Using a mouse model of medulloblastoma with reduced Patchedl function, we have identified molecular events contributing to early and late tumor lesions in the cerebellum through expression analyses. This proposal is focused on determining the roles of these factors in the developing cerebellum, the mechanisms by which they regulate cell division of the GCPs, and how they cooperate with the Shh/Patched signaling pathway to promote cellular proliferation during normal development and tumorigenesis of the cerebellum. A deeper understanding of the complex signaling networks underlying the proliferation and oncogenic transformation of the cerebellar precursor cells will reveal new targets for developing effective treatments. ? ? ?
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