A FRIZZLED HOMOLOG FUNCTIONS IN A VERTEBRATE WNT SIGNALING PATHWAY

Background: Wnts are secreted proteins implicated in cell-cell interac tions during embryogenesis and tumorigenesis, but receptors involved i n transducing Wnt signals have not yet been definitively identified. M embers of a large family of putative transmembrane receptors homologou s to the frizzled protein in Drosophila have been identified recently in both vertebrates and invertebrates, raising the question of whether they are involved in transducing signals for any known signaling fact ors. Results: To test the potential involvement of frizzled homologs i n Wnt signaling, we examined the effects of overexpressing rat frizzle d-1 (Rfz-1) on the subcellular distribution of Wnts and of dishevelled , a cytoplasmic component of the Wnt signalling pathway. We demonstrat e that ectopic expression of Rfz-1 recruits the dishevelled protein - as well as Xenopus Wnt-8 (Xwnt-8), but not the functionally distinct X wnt-5A - to the plasma membrane, Moreover, Rfz-1 is sufficient to indu ce the expression of two Xwnt-8-responsive genes, siamois and Xnr-3, i n Xenopus explants in a manner which is antagonized by glycogen syntha se kinase-3, which also antagonizes Wnt signaling. When Rfz-1 and Xwnt -8 are expressed together in this assay, we observe greater induction of these genes, indicating that Rfz-1 can synergize with a Wnt. Conclu sions: The results demonstrate that a vertebrate frizzled homolog is i nvolved in Wnt signaling in a manner which discriminates between funct ionally distinct Wnts, which involves translocation of the dishevelled protein to the plasma membrane, and which works in a synergistic mann er with Wnts to induce gene expression. These data support the likely function of frizzled homologs as Wnt receptors, or as components of a receptor complex. (C) Current Biology Ltd ISSN 0960-9822