Identification and characterization of functional modules in Lef/Tcf

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In the previous years we confirmed our hypothesis that individual Lef/Tcf family members regulate the cell-type specific response to canonical wnt-signaling. Meanwhile, it is widely accepted that the “classical view” to simply unite Lef/Tcf transcription factors as nuclear transducer of the wnt/b-catenin pathway ignores many aspects of cell- and tissue specific responses. Although we identified Hic-5 (Ghogomu et al., 2006) as novel subtype specific binding partner, many aspects of subtype specific target gene regulation remain unanswered. Similarly, other novel Tcf-binding partners including HIC1, HBP and PIAS explain the subtype-specificity only partially. Instead, novel results indicate epigenetic mechanisms as major regulatory principle for Tcf-subtype-, promoter- and cell-type specific regulation. With the identification of Xcirp as XTcf-3 specific target gene, the regulation of XTcf-4 via a Lef/Tcf binding site on its promoter and by including additional direct wnt target genes we have now the tools in our hands for a systematic analysis of epigenetic mechanisms for Tcf subtype specific target gene regulation.From an evolutionary point of view, it is interesting that evertebrates express only one Tcf while vertebrates express four Lef/Tcfs. Our previous analyses on Tcf-subtype specific functions in Xenopus allows us now to assign at least one specific aspect in early embryogenesis to one distinct Lef/Tcf family member. Thus, in reconstitution experiments we will be able to allocate ancient Lef/Tcf functions. This approach will help us to identify regions/domains important for the distinct functions. These domains shall be further characterized.