Date of Graduation
5-2015
Document Type
Dissertation (PhD)
Program Affiliation
Genes and Development
Degree Name
Doctor of Philosophy (PhD)
Advisor/Committee Chair
Vicki Huff, Ph.D.
Committee Member
Richard Behringer, Ph.D.
Committee Member
M. John Hicks, M.D., D.D.S., Ph.D.
Committee Member
Hui-Kuan Lin, Ph.D.
Committee Member
Stephanie S. Watowich, Ph.D.
Abstract
Wilms tumor is one of the most common solid tumors in children. It is an embryonic cancer of the kidney and is thought to arise from undifferentiated renal mesenchyme. However, the differentiation status of cells in the mesenchyme that can give rise to Wilms tumors is unknown. Gene expression analysis of a large panel of Wilms tumor patients has identified different subsets of Wilms tumors that are distinct in their clinical outcomes and gene expression signatures. These subsets express specific genes that correspond to different stages of differentiation during renal development, suggesting that Wilms tumors may arise from transformed cells at different states of differentiation. Wilms tumors are genetically heterogeneous, which can also affect the tumor biology and pathology. To test whether cells at different states of differentiation were tumorigenic, we used progenitor cell-type-specific Cre to introduce mutations of Wilms Tumor gene 1 (Wt1) or b-catenin into fetal kidney cells in a progenitor-specific manner. We found that the nephron progenitors but not the stroma progenitors were able to give rise to Wilms tumors and that the different types of mutations introduced into nephron progenitor cells resulted in Wilms tumors with differing histology and expression of developmentally regulated genes. Also, to investigate the mechanisms by which WT1 mutations cause a predisposition to Wilms tumors, we studied the in vivo effects of Wt1 ablation in different renal progenitor cells. We found that Wt1 ablation in stroma progenitors did not affect nephrogenesis but that Wt1 is required for nephron progenitors to undergo mesenchyme to epithelia transition.
Keywords
Wilms tumor, Kidney development, kidney progenitor, genetic mouse model, Wt1, beta-catenin, Igf2