The role of Sox4 in kidney development

Arsenault, Michel Gérard

Dissertation/Thesis

2016

Hartwig, Sunny
Wright, Glenda

Bate, Luis
Hartwig, Sunny
Martinson, Shannon
McConkey, Sandra
Bridgewater, Darren

Kamunde, Collins
Hartwig, Sunny
Wright, Glenda
Greenwood, Spencer
Martinson, Shannon
Spears, Jonathan

Doctor of Philosophy

Faculty of Veterinary Medicine. Department of Biomedical Sciences.

Biomedical Sciences

Biomedical Sciences

University of Prince Edward Island

Charlottetown, PE

Over the last decade the number of Canadians with end-stage kidney disease (ESKD) has steadily risen and there are at present more than 35,000 Canadians living with ESKD. Currently only three treatment options are available to replace the blood filtering function performed by the kidneys: hemodialysis, peritoneal dialysis and kidney transplant. A better understanding of the mechanisms involved in kidney development could hold the key to developing targeted therapies to repair and reverse damage Show moreOver the last decade the number of Canadians with end-stage kidney disease (ESKD) has steadily risen and there are at present more than 35,000 Canadians living with ESKD. Currently only three treatment options are available to replace the blood filtering function performed by the kidneys: hemodialysis, peritoneal dialysis and kidney transplant. A better understanding of the mechanisms involved in kidney development could hold the key to developing targeted therapies to repair and reverse damage caused by kidney diseases. The DNA-binding transcription factor Wilms' Tumor Suppressor-1 (WT1) plays an essential role in nephron progenitor cell differentiation during kidney development. In mice, homozygous deletion of Wt1 results in complete absence of both kidneys. Previously, chromatin-immunoprecipitation coupled to microarray identified all three members of the Sry-related high-mobility group (HMG) Box (Sox)C subfamily, namely, Sox4, Sox11 and Sox12, as novel Wt1 target genes that may regulate kidney development in vivo. Although SoxC genes play master roles in determining neuronal and mesenchymal progenitor cell fate in a multitude of developmental processes, their function in the developing kidney has been, until now, undefined. All three SoxC genes are expressed in the nephrogenic lineages during kidney development. Conditional ablation of Sox4 in nephron progenitors and their cellular descendants (Sox4neprhon- mice) results in early-onset proteinaceous glomerular injury within 2 weeks of birth progressing to end-stage renal failure within 5-9 months. An updated version of the gold standard modality to accurately, rapidly and cost-effectively quantitates nephron number in embryonic and post-natal mouse kidneys was developed. This approach was used to determine that ablation of Sox4 in nephron progenitors and their cellular descendants results in a significant reduction in nephron endowment. This reduction in nephron endowment in Sox4neprhon- mice results from the formation of fewer pretubular aggregates, likely as a result of decreased cell cycling of nephron progenitor cells. Sox4 and Sox11 were also shown to be dispensable for normal podocyte differentiation and function. Conditional deletion of both of these genes individually as well as in combination in podocytes resulted in no apparent glomerular phenotype after 6 months and does not recapitulate the phenotype observed in Sox4neprhon- kidneys. Analysis of Sox4neprhon- kidneys suggests that the genesis of glomerular injury may be activated parietal epithelial cells (aPEC). Collectively, the results presented in this thesis demonstrate that Sox4 plays multiple crucial roles in normal kidney development and function in vivo. Show less

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