Modulation of Sonic Hedgehog signaling alters cerebellar development and medulloblastoma formation
Cheng, Frances Yun
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2013-12-10
Abstract
Cerebellar development is a complex process involving the tightly regulated proliferation, specification, migration, and connectivity of thousands of neurons and glia. Perturbations in signaling pathways important for these processes can have drastic consequences, including medulloblastoma formation. In this dissertation work I have focused on Sonic Hedgehog (Shh) signaling and its role in cerebellar development and formation of medulloblastoma. Our studies have identified a novel contribution of the multipotent hindbrain roof plate cell to diverse lineages in the cerebellum and its susceptibility to oncogenic transformation by deregulated Shh signaling, which leads to medulloblastoma formation. In addition, we have determined a previously unappreciated role for Shh signaling in specialized cerebellar glial cells, which functions to sustain proliferation of neighboring neuronal precursors. Last, we identify a small molecule as a novel and potent Hh pathway antagonist in multiple cell types, including Hh-responsive medulloblastoma cells. My work therefore offers insight into the diverse roles of Shh activity in the cerebellum during development and disease, which can provide insight into brain growth and the development of targeted therapies for disease processes.