| Wnt glycoproteins play an important role in patterning the developing embryo. Binding of Wnt to its receptor initiates a signaling cascade that induces the expression of specific Wnt target genes. A central player in this signaling pathway is beta-catenin. In the presence of Wnt, beta-catenin migrates to the nucleus and binds to members of the TCF family of transcription factors. TCF and beta-catenin form a bipartite transcription factor that activates the expression of Wnt target genes. In the absence of Wnt signaling, a cytoplasmic complex that consists of the tumor-suppressor protein APC, Axin and the kinase GSK3b ensures that beta-catenin is degraded and target gene expression is turned off. The importance of this tight regulation of beta-catenin levels is illustrated by the fact that mutations in APC are frequently found in cancer. When APC is absent, beta-catenin is no longer degraded, resulting in constitutive Wnt target gene activation. The mechanism of transcriptional activation by TCF/beta-catenin is still largely unknown. Some evidence suggests that beta-catenin facilitates target gene expression by recruiting chromatin remodeling components. We are taking a genetic approach in the nematode C. elegans to study the mechanism of Wnt/beta-catenin signaling. C. elegans is a relatively simple model organism that has a number of advantages over vertebrate model systems: the short life cycle and powerful genetic tools allow genetic screens that are not feasible in higher organisms. The Wnt pathway is highly conserved in evolution and a canonical Wnt pathway also functions during C. elegans development. This pathway is needed for the expression of Wnt target genes such as the homeobox gene mab-5, and requires an interaction between BAR-1/beta-catenin and POP-1/TCF. We are currently screening for mutations that affect the Wnt dependent expression of mab-5. In addition, we have constructed mutants in which BAR-1/beta-catenin is constitutively active. We are using these mutants in genetic screens to identify additional components that are required for BAR-1 signaling. Given the high degree of conservation of the Wnt pathway, we expect that these components will have important functions in vertebrates as well. |
