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Previous studies have demonstrated that certain Wnt ligands can promote high levels of cooperative signaling in a cell type specific manner. To explore the underlying mechanism of this cooperative Wnt signaling, we performed a high-throughput screen of more than 14,000 cDNAs to identify genes that promote cooperative Wnt signaling in the context of a single Wnt ligand, Wnt2. This screen identified several homeobox factors including Msx2, Nkx5.2, and Esx1, in addition to other factors known to promote Wnt signaling including Pias4. Generation of dominant-active or dominant-negative forms of Msx2 indicate that the mechanism by which homeobox factors cooperatively promote Wnt signaling is through their ability to repress gene transcription. These data identify a broad homeobox code, which acts to increase Wnt signaling through transcriptional repression.