Screening a maternal Xenopus expression library for activities that synergize with low levels of injected β-catenin, we have isolated a clone encoding the C-terminal end of x- βTrCP-2, a highly conserved protein belonging to the F-box/WD40 family of ubiquitin-ligase specificity factors. We show that x- βTrCP-2 expression reduces dorsal axis formation in Xenopus embryos. A dominant negative mutant lacking the F-box triggers the opposite effect, inducing secondary axes and activating the expression of Wnt responsive genes in ectodermal explants. In light of the existence of βTrCP transcripts associated with the vegetal cortex, we propose that βTrCP plays a fundamental role in the establishment of the dorsal determinants during cortical rotation in Xenopus.