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Understanding the role of the Sonic Hedgehog signaling pathway in cerebellar development and medulloblastoma genesis

Dey, Joyoti (2012) Understanding the role of the Sonic Hedgehog signaling pathway in cerebellar development and medulloblastoma genesis. PhD thesis, Fred Hutchinson Cancer Research Center / University of Washington.

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Abstract

Medulloblastoma is a developmental cancer of the cerebellum. It continues to be the most common pediatric brain cancer associated with dire survival and impaired quality of life. In order to develop therapeutic interventions, it is necessary to bridge the gaps in knowledge about cerebellar development and understand how aberrations in developmental pathways lead to cancer. The Sonic hedgehog pathway (Shh) plays a pivotal role in cerebellar development and mutations leading to hyperactive signaling cause medulloblastoma. Although the fundamentals of the pathway mechanics are known, and have led to the development of mouse models to study the human disease, there are critical questions that remain to be answered. Based on pathway signatures medulloblastomas are categorized into subgroups, Shh-driven being one such subgroup. However there is significant heterogeneity even among Shh-driven medulloblastomas that necessitates understanding key differences between the various mutations and differential regulation of downstream effectors. Through the characterization of a novel mouse model of medulloblastoma, SmoA2 and comparative analyses with the existing SmoA1 model, I have demonstrated salient molecular and cellular differences between two activating mutations in the same region of a single gene. While the SmoA1 mutation leads to medulloblastoma in adult mice, in addition to cancer, the SmoA2 mutation causes severe defects early in cerebellar development. The transcriptional profiles downstream of these two mutations and biological processes affected are distinct. An unexpected finding from the SmoA2 model is the preservation of normal cerebellar function despite a completely disrupted cytoarchitecture challenging the notion that stereotypical organization of the cerebellum is critical for its function. My second aim was to identify molecules that interact with the Shh pathway in development and disease. Toward this goal, I discovered a previously unkown expression pattern of MyoD in the proliferative phase of the developing cerebellum as well as in mouse medulloblastoma. MyoD, a myogenic differentiation factor has been known to be exclusive to the skeletal muscle lineage. I demonstrate MyoD functions as a novel haploinsufficient tumor suppressor in the context of medulloblastoma with potential clinical significance.

Item Type: Thesis (PhD)
Subjects: Cellular and Organismal Processes > Cell Physiology > Cell communication
Cellular and Organismal Processes > Development
Depositing User: Craig Johansen
Date Deposited: 01 Jun 2012 19:34
Last Modified: 01 Jun 2012 19:34
URI: http://authors.fhcrc.org/id/eprint/564

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