Benedykcinska, AM; (2014) Multiple Roles of β-Catenin in Brain Development and Tumourigenesis. Doctoral thesis , UCL (University College London).

Abstract

β-catenin is a multifunctional protein with roles in Wnt pathway signal transduction and in cell adhesion. While the normal function of β-catenin is important for CNS development, Wnt pathways have also been intrinsically linked to cancer. Here, the multiple roles of β-catenin in CNS development and in brain tumour pathogenesis were investigated. All experiments used a mouse model where a dominant active form of β-catenin can be induced by Cre mediated recombination of the exon 3 of the CATNNB gene. Three models were established to analyse the effects of dominant active β-catenin: (i) during development with En2Cre, in the midbrain-hindbrain regions, (ii) in mature (L7Cre) Purkinje neurons, and (iii) in adult stem cells using Cre delivery into the SVZ using an established and a specifically developed novel method. En2Cre;β‐cateninlox(ex3) mice express mutant β-catenin in the midbrain-hindbrain junction during early brain development. Although En2 is expressed between E8 and E12.5, the precise timing and duration of stabilized β‐catenin is not known. At later stage, these mice showed decreased motor performance, caused by a significant defect in the vermis region. This phenotype could be rescued by deletion of p53 gene, pointing at a potential role of p53/β-catenin cross-talk. In contrast, constitutive activation of β-catenin in mature cerebellar Purkinje neurons using the L7Cre; β-cateninlox(ex3) model, does not cause cell death or dysfunction of these neurons. To target SVZ stem/progenitor cells, we used an established model with adenovirus-Cre mediated recombination and we developed a highly selective approach through direct, intraventricular injection of Endoxifen into GLAST-Cre(ERT2) mice. Both approaches resulted in similar phenotypes and latencies to tumour development, and required at least one additional tumour suppressor to be inactivated simultaneously to cause brain tumours. The results suggest that β-catenin has diverse effects during different developmental stages. During early development, it causes widespread cell death, whilst no effect is seen in mature cells. In adult SVZ progenitor cells it has no effect unless tumour suppressor genes such as p53 or PTEN are concomitantly inactivated, resulting in formation of brain tumours.

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