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.
| Identifer | oai:union.ndltd.org:VANDERBILT/oai:VANDERBILTETD:etd-12102013-063407 |
| Date | 10 December 2013 |
| Creators | Cheng, Frances Yun |
| Contributors | Bruce Carter, Robert Coffey, Chris Wright, Ethan Lee |
| Publisher | VANDERBILT |
| Source Sets | Vanderbilt University Theses |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.vanderbilt.edu/available/etd-12102013-063407/ |
| Rights | restricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to Vanderbilt University or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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