XCtBP is a XTcf-3 co-repressor

Studies in many systems have established the importance of the Wnt pathway in regulating numerous processes during embryonic development, as well as cell proliferation during later life (Cadigan and Nusse, 1997; Moon et al., 1997; Cox and Peifer, 1998; Wodarz and Nusse, 1998). A key step in the activation of Wnt-responsive genes is the binding of the transcriptional co-activator β-catenin/Armadillo to DNAbinding transcription factors of the Tcf/Lef family (Behrens et al., 1996; Huber et al., 1996; Molenaar et al., 1996; Brunner et al., 1997; van de Wetering et al., 1997). In early Xenopus development, for example, the Wnt pathway activates the expression of two homeobox genes, siamois (Lemaire et al., 1995; Brannon and Kimelman, 1996; Yang-Snyder et al., 1996) and twin (Laurent et al., 1997) and the signaling factor Xnr3 (Smith et al., 1995) as an early step in the process that establishes the dorsal-ventral and anterior-posterior axes (Moon and Kimelman, 1998). Siamois, twin and Xnr3 contain Tcf/Lef binding sites in their promoters (Brannon et al., 1997; Laurent et al., 1997; McKendry et al., 1997; Fan et al., 1998), suggesting that the early dorsal accumulation of β-catenin in the Xenopus embryo leads to the direct activation of these genes (Larabell et al., 1996; Moon and Kimelman, 1998). Surprisingly, the elimination of all three Tcf/Lef binding sites from the siamois promoter results in the elevated expression of the gene (Brannon et al., 1997), indicating that Tcf/Lef proteins could function as repressors (reviewed by Bienz, 1998). Thus, the endogenous maternal Xenopus Tcf/Lef family member, XTcf3 (Molenaar et al., 1996), was proposed to repress siamois on the ventral side of the embryo, whereas the enhanced dorsal levels of β-catenin were proposed to overcome this repression, leading to the dorsal expression of siamois (Brannon et al., 1997). Similar results were obtained in Drosophila, where the elimination of dTcf binding sites in the Ultrabithorax gene expanded its domain of expression (Riese et al., 1997). Moreover, mutants in the Caenorhabditis elegans Tcf homologue, pop-1, produce a phenotype equivalent to constitutive Wnt signaling, indicating that POP-1 also functions as a transcriptional repressor (Rocheleau et al., 1997; Thorpe et al., 1997). In Xenopus, ectopic expression of XTcf-3 and mouse LEF1 produce significantly different results. When XTcf-3 is ectopically expressed on the ventral side of Xenopus embryos, no alteration in development is observed (Molenaar et al., 1996). In contrast, ventral ectopic expression of LEF-1 results in the formation of a partial secondary axis (Behrens et al., 1996). Since β-catenin levels are low on the ventral side of Xenopus embryos (Larabell et al., 1996; Schneider et al., 1996), we suspected that the ectopically supplied LEF-1 might function by displacing the endogenous XTcf-3, an event which would derepress the siamois promoter if LEF-1 lacked the repressing function of XTcf-3. 3159 Development 126, 3159-3170 (1999) Printed in Great Britain © The Company of Biologists Limited 1999 DEV5316