The Wnt/beta-catenin signaling pathway controls embryonic development and adult stem cell maintenance through the regulation of transcription. Failure to downregulate Wnt signaling can result in embryonic malformations and cancer, highlighting the important role of negative regulators of the pathway. The Wnt pathway activates several negative feedback targets, including axin2 and Dkk1, that function at different levels of the signaling cascade; however, none have been identified that directly target active beta-catenin/Tcf1 transcriptional complexes. We show that Zfp703 is a Wnt target gene that inhibits Wnt/beta-catenin activity in Wnt reporter assays and in Wnt-dependent mesoderm differentiation in embryonic stem cells. Zfp703 binds directly to Tcf1 to inhibit beta-catenin/Tcf1 complex formation and does so independently of the Groucho/Tle transcriptional corepressor. We propose that Zfp703 is a novel feedback suppressor of Wnt/beta-catenin signaling that functions by inhibiting the association of beta-catenin with Tcf1 on Wnt response elements in target gene enhancers.
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