Wnts are secreted proteins which are known to be important in the processes by which fertilized eggs develop into embryos. More specifically, Wnts are likely to be involved in the processes by which spherical vertebrate eggs develop into bilaterally symmetrical embryos, and later in development they may be involved in the processes by which regions of the embryo express different genes, and differentiate into distinct cell types. When Wnts are expressed inappropriately in mammary epithelial cells of mice and humans, they may contribute to transformation and to cancer. In both normal embryos and during cell transformation Wnts are likely to act as ligands which activate receptor- mediated signaling pathways which lead to suppression of the activity of glycogen synthase kinase-3, consequently alleviating its repression of the cytoplasmic protein beta-catenin which in turn changes gene expression and cell fate. In the present proposal, four specific aims are proposed which will directly test the roles of Wnts in the above-mentioned processes of mouse mammary cell transformation and in vertebrate development.
Aim 1 tests the ability of a dominant negative Wnt ligand to block Wnt- mediated transformation, and to reverse transformation of a mouse mammary cell line. Thereafter, this cell line is used as a system for developing improved and potentially therapeutic reagents.
Aim 2 employs the dominant negative Wnt ligands to test the roles of Wnts in specification of mesoderm through a loss/reduction-of-function approach, and Aim 3 extends this type of analysis to test a recent hypothesis regarding the role of Wnts in patterning neural gene expression along the anterior- posterior axis.
Aim 4 employs the dominant negative Wnt, as well as a green Fluorescent tagged beta-catenin to explore in living cells how Wnt signals lead to changes in the subcellular distribution of signaling molecules in the Wnt pathway.
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