TheDrosophilaEcR-Hippo component Taiman promotes epithelial cell fitness by control of the Dally-like glypican and Wg gradient

Abstract

ABSTRACTRapidly dividing cells can eliminate slow growing neighbors through the apoptotic process of cell competition. This process ensures that only high fitness cells populate embryonic tissues and is proposed to underlie the ability of oncogene-transformed cells to progressively replace normal cells within a tissue. Patches of cells in theDrosophilawing disc overexpressing the oncogenic Taiman (Tai) transcriptional coactivator kill normal neighbors by secreting Spätzle ligands that trigger pro-apoptotic Toll signaling in receiving cells. However, extracellular signaling mechanisms responsible for elimination of slow growing cells by normal neighbors remain poorly defined. Here we show that slow growing cells with reduced Tai (Tailow) are killed by normal neighbors through a mechanism involving competition for the Wingless (Wg/Wnt) ligand. Elevated Wg signaling significantly rescues elimination of Tailowcells in multiple organs, suggesting that Tai may normally promote Wg activity. Examining distribution of Wg components reveals that Tai promotes extracellular spread of the Wg ligand from source cells across the wing disc, thus ensuring patterned expression of multiple Wg-regulated target genes. Tai controls Wg spread indirectly through the extracellular glypican Dally-like protein (Dlp), which binds Wg and promotes its extracellular diffusion and capture by receptors. Data indicate that Tai likely controls Dlp at two levels: transcription ofdlpmRNA and Dlp intracellular trafficking. Overall, these data indicate that the Tai acts through Dlp to enable Wg transport and signaling, and that cell competition in the Tailowmodel arises due to inequity in the ability of epithelial cells to sequester limiting amounts of the Wg growth factor.