Abstract

ABSTRACTWilms' tumours, paediatric kidney cancers, are the archetypal example of tumours caused through the disruption of normal development. The genetically best-defined subgroup of Wilms' tumours is the group caused by biallelic loss of the WT1 tumour suppressor gene. Here, we describe a developmental series of mouse models with conditional loss of Wt1 in different stages of nephron development before and after the mesenchymal-to-epithelial transition (MET). We demonstrate that Wt1 is essential for normal development at all kidney developmental stages under study. Comparison of genome-wide expression data from the mutant mouse models with human tumour material of mutant or wild-type WT1 datasets identified the stage of origin of human WT1-mutant tumours, and emphasizes fundamental differences between the two human tumour groups due to different developmental stages of origin.

Highlights

  • Wilms’ tumours (Wilms, 1899) is a paediatric kidney cancer that affects 1:10,000 children, usually before the age of five

  • We demonstrate that Wt1 is essential for normal development at all kidney developmental stages under study

  • Use of a Cre allele expressed from the endogenous Pax8 locus (Bouchard et al, 2004) resulted in scattered eYFP-positive cells in the E11.5 metanephric mesenchyme and a strong signal in the condensed mesenchyme and in the ureteric bud

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Summary

Introduction

Wilms’ tumours (Wilms, 1899) is a paediatric kidney cancer that affects 1:10,000 children, usually before the age of five (recently reviewed in Hohenstein et al, 2015). The cells that are induced to differentiate undergo a mesenchymal-to-epithelial transition (MET) under control of Wnt (Kispert et al, 1998; Stark et al, 1994) to form the epithelialized renal vesicle, probably mediated by the noncanonical Wnt-Ca2+-NFAT pathway (Burn et al, 2011; Tanigawa et al, 2011) Disruption of this MET is believed to be a central event in the development of Wilms’ tumours (Hohenstein et al, 2015). The renal vesicle becomes patterned along the proximal-distal axis, connects to the ureteric bud at its distal end and through the comma and S-shaped body stages develops into the mature nephron consisting of distal tubule, loop of Henle, proximal tubule and the glomerulus, containing the filtering podocytes This nephron induction, differentiation and maturation process is repeated every time the ureteric bud branches and new tips are formed

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