Cis-inhibition of Notch by Delta controls follicle formation inDrosophila melanogaster

Daughters of stem cells often differentiate sequentially in response to inputs from various signalling molecules. We focus on the regulation of Notch signalling in the Drosophila germarium, which contains several somatic stem cells. Stem cell siblings produce polar cell (pc) or main body follicular cells (MBFC) precursors as they surround the germline and form follicles. Notch has been shown to be activated in at least one of the stem cell siblings and in the pc precursors by a Delta signal produced by the germline cells. However, removing N in the soma leads to abnormal follicles while removing Delta from the germline does not, indicating that the tissue-specific requirement needs to be re-examined. Here, we demonstrate that Delta in the soma downregulates Notch activity via a cis-inhibition mechanism. Somatic Delta prevents Notch from being strongly activated by germline Delta, resulting in the maintenance of an undifferentiated state. In addition, we show that somatic Delta is required to activate Notch in the pc precursors and that its activity is more efficient in initiating pc differentiation than germline Delta. Thus, Notch activity in the germarium depends on both germline and somatic Delta, explaining why removing Delta from the germline does not phenocopy Notch phenotype. Finally, our work provides a novel example of the importance of the regulation of Notch activity through a cis-inhibitory mechanism. Significance StatementStem cells produce daughter cells that progressively adopt different identities through the activities of signalling pathways, such as the Notch pathway. The activity of this pathway depends on the ability of the ligand produced by a cell to activate the Notch receptor expressed by a neighbouring cell. In vertebrates and invertebrates, Notch has been shown to either promote cell fate acquisition or maintenance of an undifferentiated state, depending on its regulation. Here, we investigate the regulation of Notch in stem cell daughter cells in Drosophila. We demonstrate that its activity is downregulated in these cells through an mechanism, called the cis-inhibition mechanism, meaning that Notch is blocked by the ligand produced within the same cell.