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Title The Functional Role of Stromal Β-catenin in the Pathogenesis of Renal Dysplasia and Kidney Devolpment
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Publication Date
Date Available
Degree PhD
Degree Level doctoral
University/Publisher McMaster University
Abstract

Renal dysplasia is a disease characterized by developmental abnormalities of the kidney that affect 1 in 250 live births. Depending on the severity of the renal abnormalities, this disorder can lead to childhood kidney failure, adult onset chronic kidney disease, and hypertension. Currently, the best treatment options for patients with renal dysplasia are renal dialysis and kidney transplant. Our limited understanding of the pathogenesis of renal dysplasia has prevented the development of better treatment strategies for those patients. A hallmark of renal dysplasia is an expansion of loosely packed fibroblast cells, termed renal stroma. Markedly elevated levels of β-catenin have been reported in the expanded stromal population in patients with dysplastic kidneys. Yet, the contribution of stromal β-catenin to the pathogenesis of renal dysplasia is not known. Additionally, the role of stromal β-catenin in the developing kidney is not clear. The overall hypothesis of this PhD thesis is that β-catenin in stromal cells controls key signalling molecules that regulate proper kidney development. Furthermore, we hypothesize that elevated levels of β-catenin contribute to the pathogenesis of renal dysplasia. To mimic the human condition, we generated a mouse model that overexpresses β-catenin specifically in the stroma (termed β-catGOF-S). In addition, to gain a better understanding of its role in kidney development, we generated a second mouse model deficient for β-catenin exclusively in stromal cells (termed β-catS-/-). The goal of this study is to utilize these models to understand the role of stromal β-catenin in kidney formation and investigate its contribution to renal dysplasia. The first objective defines the contribution of stromal β-catenin to the genesis of renal dysplasia. We provide evidence for a mechanism whereby the overexpression of stromal β-catenin disrupts proper differentiation of stromal progenitors and leads to an expansion of stroma-like fibroblast cells and vascular morphogenesis defects. In the second objective, we establish a mechanism where stromal β-catenin modulates Wnt9b signaling in epithelial cells to control proliferation of the nephron progenitors. In the third objective, we define a role for stromal β-catenin in proper formation and survival of the medullary stroma. Finally, in a technical report, we outline a protocol to isolate stromal cells in the developing kidney and provide potential downstream applications to further our understanding of stromal β-catenin in the developing kidney. Taken together, our findings establish a crucial role for stromal β-catenin in the genesis of renal dysplasia and demonstrate, using two mouse models, that stromal β- catenin must be tightly regulated for proper formation of the stroma lineages and development of the kidney.

Thesis

Doctor of Philosophy (PhD)

Subjects/Keywords Kidney Development; B-catenin
Contributors Bridgewater, Darren; Medical Sciences (Growth and Development)
Language en
Country of Publication ca
Record ID handle:11375/20409
Repository mcmaster
Date Indexed 2020-08-12

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…Ph.D. Thesis – Felix Boivin-Laframboise McMaster University – Medical Sciences PREFACE This is a “sandwich” style thesis. Chapter 1 is a general introduction that includes parts of a review article I have published during my PhD. To provide…

…limitations of the work presented in this thesis are discussed in Chapter 6. viii Ph.D. Thesis – Felix Boivin-Laframboise McMaster University – Medical Sciences TABLE OF CONTENTS ABSTRACT…

…55 ix Ph.D. Thesis – Felix Boivin-Laframboise McMaster University – Medical Sciences Stromal Defects Result in Disrupted Vasculature Morphogenesis ............................ 59 Human dysplastic tissue exhibits similar stromal abnormalities…

…Laframboise McMaster University – Medical Sciences CHAPTER 5 - Technical Report: Isolation of Renal Stromal Cells From WT AND βcat-/- Mouse Strains ......................................................................................................... 172…

…198 xi Ph.D. Thesis – Felix Boivin-Laframboise McMaster University – Medical Sciences LIST OF FIGURES CHAPTER 1 Figure 1.1 – Gross anatomy and basic structure of the kidney ............................................... 5 Figure 1.2 - Basic…

…Thesis – Felix Boivin-Laframboise McMaster University – Medical Sciences Figure 3.8 - β-catS-/- mutants demonstrate altered Wnt9b signaling to the condensing mesenchyme…

…of the stromal markers in FACS stromal cells.................... 189 xiii Ph.D. Thesis – Felix Boivin-Laframboise McMaster University – Medical Sciences LIST OF SUPPLEMENTAL FIGURES CHAPTER 2 Supplemental Figure S2.1 – Characterization of β…

McMaster University – Medical Sciences LIST OF ABBREVIATIONS A ad Amph APC Aqp-3 b B2M Bag3 BAT Bax Bcl2 Bcl2l1 Birc5 Bmp4 BrdU CD44 cDNA ChIP Cited1 CKD cm Co-IP cs DAB DAPI Dchs1 Dkk1 DMEM DNA E Ecm1 Emx2 Erg ESR1 Eya1 FACS Apoptosis Adrenal Gland…

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