Distant Activation Of Notch Signaling Induces Stem Cell Niche Assembly

Here we show that multiple modes of Notch signaling activation specify the complexity of spatial cellular interactions necessary for stem cell niche assembly. In particular, we studied the formation of the germline stem cell niche in Drosophila ovaries, which is a two-step process whereby terminal filaments are formed first. Then, terminal filaments signal to the adjacent cap cell precursors, resulting in Notch signaling activation, which is necessary for the lifelong acquisition of stem cell niche cell fate. The genetic data suggest that in order to initiate the process of stem cell niche assembly, Notch signaling is activated among non-equipotent cells via distant induction, where germline Delta is delivered to somatic cells located several diameters away via cellular projections generated by primordial germ cells. At the same time, to ensure the robustness of niche formation, terminal filament cell fate can also be induced by somatic Delta via cis- or trans-inhibition. This exemplifies a double security mechanism that guarantees that the germline stem cell niche is formed, since it is indispensable for the adjacent germline precursor cells to acquire and maintain stemness necessary for successful reproduction. These findings contribute to our understanding of the formation of stem cell niches in their natural environment, which is important for stem cell biology and regenerative medicine.Author summaryAdult organs often contain a stem cell niche that maintains stem cells necessary for the replenishment of different types of terminally differentiated cells that are continuously lost. This study reveals that various modes of Notch signaling activation induce the formation of the germline stem cell niche in Drosophila. We show for the first time that even among non-equipotent cells, Notch signaling can be trans-activated via distant induction mode, where the ligand Delta is delivered via cellular protrusions to the somatic stem cell niche precursors located several cell diameters away. Moreover, there is a second security mechanism controlled by the soma that additionally ensures that the stem cell niche is formed. In the stem cell niche precursors, Notch signaling can be locally inhibited by the somatic Delta. While Notch signaling trans-inhibition has been proposed via mathematical modelling, our findings show that a group of cells that have high Delta can be seen in a living organism, confirming that this mode of Notch signaling inhibition by trans-Delta exists in vivo. This work provides significant advances in the understanding of Notch signaling and the stem cell niche formation, which is important for the fields of stem cell biology and regenerative medicine.