Wnt genes encode a large family of secreted signaling molecules essential for development and oncogenesis. In Drosophila, the wingless (wg) gene is essential for embryonic development, whereas in mice, the wnt genes are required for brain development, mesoderm formation, kidney organogenesis and limb morphogenesis. In addition, ectopic activation of certain wnt genes causes the formation of mammary tumors, providing a potential model for studying human breast cancer. Although progress has been made in understanding Wnt signal transduction, essential questions concerning the mechanism of Wnt signaling remain to be answered. In particular, it was only very recently that a Wg receptor was discovered as a member of the Frizzled (Fz) family of seven transmembrane receptors. While this implies that the large family of Fz proteins are receptors for Wnt molecules, the scarcity of soluble Wnt proteins complicates the investigation of Wnt-Fz interactions. The Xenopus embryo provides a unique model system to study Wnt signal transduction. Expression of a number of Wnt molecules and manipulation of known intracellular Wnt signaling components results in duplication of the embryonic axis. This not only implicates the Wnt signal transduction pathway in vertebrate embryonic patterning, but also provides a dramatic and facile assay for studying the molecular mechanism of Wnt signaling and for identifying novel components in Wnt signal transduction. Because RNA or DNA injection into embryos is precisely controlled and bypasses the requirement of soluble Wnt proteins, and because axis duplication is readily scored, the Xenopus embryo system has made significant contributions to our understanding of Wnt signaling. Using this system, we identified glycogen synthase kinase-3 as a component in the conserved Wnt signal transduction pathway, and identified a member of the mammalian Fz protein family, hFz5, as a candidate receptor for Wnt-5A. Experiments are proposed using Wnt-5A/hFz5 coupling in Xenopus embryos as a model system to address two critical questions: 1) What is the mechanism governing the specificity of Wnt-Fz coupling? 2) How does a Fz protein transduce the Wnt signal? These experiments should provide a better understanding of Wnt signal transduction in development and malignancy.
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