UCSF

The adult stem cell niche microenvironment is essential for maintenance and self renewal of the cell within that environment, ensuring a consistent population of stem cells available for regeneration of differentiated daughter cells. In the Drosophila ovary, follicle stem cells (FSCs), produce and maintain the epithelium of the eventual oocytes. These FSCs reside at the anterior edge of the tissue where they regularly divide throughout oogenesis. Like many epithelial tissues, the FSCs require the Wnt/Wingless and EGF signaling pathways for self-renewal. Abrogation of either pathway leads to FSC loss whereas constitutive activation of either pathway inhibits daughter cell differentiation. These findings demonstrate that precise activation of Wingless and EGF signaling within the narrow range of the FSC niche is essential to preserve stem cell identity while allowing daughter cells to differentiate. However, it remains unclear how this specificity is achieved, and how these signals cooperate to maintain FSC self renewal. We found that the specificity of Wingless signaling is not due to an inability of FSC daughter cells to activate Wingless signaling or to cross-talk with the Hedgehog or Notch pathways. Instead, our data suggest that the Wingless ligand is locally delivered by nearby niche cells and spatially restricted to FSCs. We also found that FSCs with impaired Wingless signaling lack pERK, an indicator of EGF signaling, suggesting that Wingless signaling functions upstream of EGF signaling in a hierarchy of self-renewal pathways. Finally, we found that overactive EGF signaling can partially rescue the FSC loss caused by knocking out wingless and that wingless promotes transcription of the EGF ligand spitz. Collectively, these findings demonstrate that the specific signal Wingless acts upstream of EGFR to maintain FSCs. These studies will contribute to our understanding of how epithelial stem cells are maintained both specifically and robustly, especially in a dynamic niche environment.