Ródenas Cuadrado, P.M.; (2011) Generation and analysis of mouse models of aberrant β-catenin function. Doctoral thesis , UCL (University College London).

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Abstract

The key component of the Wnt/β-catenin pathway is β-catenin, a 780 amino acid protein which was originally identified as a component of E-cadherin junctions, where it links E-cadherin with α-catenin and consequently to the actin cytoskeleton. In the absence of Wnt signalling, cytoplasmic β-catenin is phosphorylated and subsequently degraded by ubiquitinylation. Activation of Wnt signalling stabilises cytoplasmic β-catenin, which translocates into the nucleus where it binds to nuclear transcription factors TCF/LEF and regulates the expression of over thirty genes, including cell cycle activating genes. The Wnt/β-catenin pathway is essential for nervous system development and it is aberrantly active in common malignant tumours of the central nervous system, such as glioblastoma in adults and medulloblastoma in children. We have generated a mouse model expressing a Cre-recombinase-inducible form of degradation-resistant (oncogenic) β-catenin. We generated compound mutant mice to activate the Wnt/β-catenin pathway in specific brain regions and during several developmental time points. Compound mutant transgenic mice expressed dominant active β-catenin in vivo, but did not show developmental abnormalities or brain tumours even in combination with inactivated p53 alleles. Similarly, neural stem cells expressing dominant active β-catenin did not show a growth advantage or altered self-renewal. We attributed these results to low level expression of dominant active β-catenin. In addition, we later acquired mice that carry an inducible deletion of the exon 3 of β- catenin (containing the phosphorylation site). Expression of this form of β-catenin did not increase neural stem cell growth and self-renewal. However, in vivo expression results in brain malformation and lethality depending on the cells in which β-catenin was activated, however, recombination in adult stem cells in vivo did not result in brain tumours.

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