Degree Type

Dissertation

Date of Award

2015

Degree Name

Doctor of Philosophy

Department

Genetics, Development and Cell Biology

Major

Molecular, Cellular and Developmental Biology

First Advisor

Maura McGrail

Abstract

Brain and central nervous system (CNS) cancers are the leading cause of cancer-related death in children (Ostrom QT et al., 2015). Low-grade brain and CNS tumors that require minimal surgical resection due to their location in critical regions are associated with long-term morbidity throughout the life of the child (Armstrong GT et al., 2011). Children diagnosed with high-grade, aggressive brain and CNS tumors generally have a poor outcome and suffer significant deficits in neurological and neuroendocrine function as a result of intensive therapy (Fangusaro J et al., 2012). Effective, targeted therapeutics for the treatment of pediatric brain and CNS cancer are needed. Gaining a better understanding of the molecular mechanisms underlying pediatric brain and CNS cancer initiation and progression will benefit the development of therapeutics. Animal models are an important component for the improvement of our understanding of the biology of these cancers (Huszthy PC et al., 2012). The zebrafish has recently emerged as a system for modeling human diseases including brain and CNS cancers. We have characterized two distinct zebrafish brain and CNS tumor models, a low-grade, glial-like tumor model and a high-grade CNS primitive neuroectodermal-like tumor model. The transgenic Tg(flk1:RFP)is18 zebrafish line develops low-grade glial-like tumors in the optic pathway including the retina, optic nerve and optic tract. These tumors exhibited histological features similar to those observed in human pediatric pilocytic astrocytoma. Differential gene expression analysis revealed a neuroglial progenitor signature in the tumors of the retina. The second brain tumor model helped establish the use of nuclease-mediated somatic mutagenesis in zebrafish for the study of tumor suppressor function in cancer. In this model we generated genetic mosaic adults using TALENs targeting the rb1 (retinoblastoma1) tumor suppressor. These mosaic adults developed predominantly undifferentiated, primitive neuroectodermal tumors (67% of tumors) as well as differentiated, glial-like tumors (33% of tumors). This was the first demonstration that somatic inactivation of a tumor suppressor causes cancer in zebrafish and highlighted the utility of site-specific nucleases as a rapid, simple, and cost efficient method to screen potentially hundreds of candidate tumor suppressor genes that impact tumorigenesis. These models will be useful for the study of pediatric brain and CNS tumorigenesis.

Copyright Owner

Staci Lyn Solin

Language

en

File Format

application/pdf

File Size

141 pages

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