Roles of Wnt signalling pathway components in embryonic development and disease.

摘要

The Wnt signalling pathway is essential for normal development of a wide variety of species. Signalling through this pathway has been shown to be important for proper differentiation and patterning, and deregulation of this pathway in adults is tumorigenic. Activation of the pathway typically leads to changes in gene expression mediated by the stabilization of the transcriptional activator beta-catenin Overexpression or mutational induction of this protein results in inappropriate modulation of a variety of genes, many of which are involved in growth control, thus contributing to cancer progression. Further understanding of how this pathway elicits its effects should aid in the identification of new targets for therapeutic strategies.; The capacity of beta-catenin to induce tumorigenesis in the mammary gland has been demonstrated in mouse models. A variety of mammary tumor pathologies are induced by beta-catenin and these appear to be dependent upon the manner in which beta-catenin is stabilized. In addition, subsets of tumors appear to have arisen through deregulation of beta-catenin activity within the mammary stem cell compartment.; Stabilization of beta-catenin is often an early event in cancer progression, and identification of direct transcriptional targets of beta-catenin would advance our understanding of this process. A screen to identify of novel transcriptional targets of beta-catenin was conducted using large-scale microarray analyses and overexpression of beta-catenin in normal human mammary epithelial cells. Interestingly, genes encoding RXRalpha and RBP1-like proteins identified via this approach as potential beta-catenin targets.; In the absence of Wnt signalling, beta-catenin is held in check through phosphorylation-dependent ubiquitinylation. The protein kinase that triggers this degradation signal is glycogen synthase kinase-3. Inactivation of one of the two genes of GSK-3 GSK-3-beta, results in embryonic lethality in mice. This lethality is the result of enhanced sensitivity of hepatocytes to tumor necrosis factor-alpha-induced apoptosis. However, subsets of GSK-3beta embryos survive liver degradation at midgestation and live to term, subsequently dying perinatally. In addition, GSK-3beta heterozygous animals also exhibit perinatal lethality. Analysis of these animals has revealed additional developmental defects, such as omphalocele and heart defects, including double outlet right ventricle, septal defects and ventricular wall thickening.; Together, these findings constitute the body of a thesis submitted in partial fulfillment of requirements for the degree of Doctor of Philosophy in the Graduate Department of Medical Biophysics at the University of Toronto.