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Wnt signaling is an ancient signaling pathway that has accompanied the emergence of metazoans and is key to many developmental, physiological, and disease processes. Similar to other signaling pathways, gene families for both Wnt ligand and its corresponding Frizzled receptor have undergone extensive expansion during metazoan evolution. Vertebrate genomes harbor 19 closely related Wnt genes as well as 10 Frizzled genes. Gene duplication is typically considered a major driving force in the evolution of new biological functions through neo- or subfunctionalization of emerging paralogs. How this functional diversification of Wnt ligands is structurally and molecularly organized, however, remains poorly understood. The Wnt/Frizzled molecular interaction is mediated by residues conserved across both families. This promiscuous interaction is incompatible with monospecific recognition and …