Transduction of the Wnt/Wingless signal
Several signalling cascades can be triggered by the binding of Wnt proteins to their receptors on the receiving cells; the best studied of these is the so-called canonical pathway, which regulates the expression of Wnt target genes through the stabilization of β-catenin (Armadillo (Arm) in Drosophila). While we are examining various aspects of this signalling cascade, our efforts are concentrated on deciphering the nuclear events that dictate target gene expression.
One specific research focus is elucidating the significance of the N-and C-terminal transcriptional outputs from β-catenin. When β-catenin becomes DNA-tethered by LEF/TCF it coordinates the transcription of Wnt responsive target genes by RNAPII using a catalogue of interacting auxiliary transcription components. These interactions are mediated by scaffolding platforms in the C-terminus and an N-terminal branch mediated by the recruitment of the potent transcriptional activator Pygopus by BCL9/Lgs.
As part of an ongoing effort to complete the identification of signalling and regulatory components in the Wnt pathway we have improved the tools for refined genetic screens. In addition to genetic approaches we are also utilizing technologies, such as mass spectrometry, to identify new players that interact with known ones. We can also use mass spectrometric tools, such as prototypic peptides, to characterize the changes occurring in the known complexes in response to pathway activation. Combining such approaches has the power to uncover components required for all aspects of Wg signalling: secretion, transport, transduction, and transcriptional activation of target genes.
Brunner et al. (1997) “pangolin encodes a Lef-1 homologue that acts downstream of Armadillo to transduce the Wingless signal in Drosophila” Nature 385 829-33
Gerlitz and Basler (2002) "Wingful, an extracellular feedback inhibitor of Wingless" Genes Dev 16 1055-9
Kramps et al. (2002) "Wnt/wingless signaling requires BCL9/legless-mediated recruitment of pygopus to the nuclear beta-catenin-TCF complex" Cell 109 47-60
Schweizer et al. (2003) "Requirement for Pangolin/dTCF in Drosophila Wingless signaling" Proc Natl Acad Sci U S A 100 5846-51
Hoffmans and Basler (2004) "Identification and in vivo role of the Armadillo-Legless interaction" Development 131 4393-400
Hoffmans et al. (2005) "Pygopus and legless provide essential transcriptional coactivator functions to armadillo/beta-catenin" Curr Biol 15 1207-11
Städeli and Basler (2005) "Dissecting nuclear Wingless signalling: recruitment of the transcriptional co-activator Pygopus by a chain of adaptor proteins" Mech Dev 122 1171-82
Mosimann et al. (2006) "Parafibromin/Hyrax activates Wnt/Wg target gene transcription by direct association with beta-catenin/Armadillo" Cell 125 327-41
Städeli et al. (2006) "Transcription under the control of nuclear Arm/beta-catenin" Curr Biol 16 R378-85