Genetic and developmental interactions between the genes encoding Wilms tumour 1 (Wt1) and β-catenin (Ctnnb1)

Özdemir, Derya Deniz (2010). Genetic and developmental interactions between the genes encoding Wilms tumour 1 (Wt1) and β-catenin (Ctnnb1). PhD thesis The Open University.

DOI: https://doi.org/10.21954/ou.ro.0000f8c3

Abstract

Wilms’ tumour is a childhood kidney cancer which results from misdevelopment of the kidney. Inactivating mutations in the WT1 tumour suppresor gene are responsible for 15-20 % of cases. This subset of Wilms’ tumour was also shown to be strongly associated with activating mutations in β-catenin. In contrast to most types of cancer where the mutation is found in any of four phosphorylation sites on β-catenin, Wilms tumours show a clear preferential selection for a Ser45 mutation, accounting for 90% of the tumours. Based on this, we hypothesize that there are fundamental differences between the effects of different β-catenin mutations, challanging the prevailing dogma. In order to test this hypothesis, I generated an inducible β-catenin allelic series in ES cells and generated mice from these cells. Both expression of endogenous β-catenin target genes in ES cells and in vivo analysis of mice homozygous for these activated β-catenin mutant alleles revealed differences, supporting our hypothesis. As both Wt1 and β-catenin are essential in normal kidney development, and found mutated in the same tumour samples, I analysed the effect of activating mutations of β-catenin on Wt1- deficient background kidneys. Surprisingly, a partial rescue of the Wt1-deficient phenotype was shown in 3 day organ culture and in E l8.5 kidney sections and confirmed by marker analysis via Real Time PCR. The implications of these findings for development, tumour biology and signalling pathways are discussed.