Abstract
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.
Highlights
The Notch pathway is an evolutionarily conserved signaling pathway that presents a great assortment of complex behaviors in various developmental situations
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
Summary
The Notch pathway is an evolutionarily conserved signaling pathway that presents a great assortment of complex behaviors in various developmental situations. Among a group of equivalent cells, Notch signaling activation induces mutually exclusive cell fates in the adjacent cells in a process called “lateral inhibition” In this case, the membrane-localized Notch ligand (Delta or Serrate) binds to the Notch receptor on the membrane of the neighboring cell. With the help of mechanical forces, Delta-Notch interaction causes Notch receptor cleavage and translocation of its intracellular domain to the nucleus There it serves as a transcriptional co-factor that activates expression of Notch-dependent genes, which include repressors of Delta ligand [4,5,6]. It has been shown that in the epithelial cells within imaginal discs, long-range Notch lateral inhibition exists, which is mediated by Delta-promoted planar filopodia These dynamic filopodia transmit intermittent Delta-Notch signaling, which refines Notch signaling during mechanosensory bristle formation and even can promote tumorigenesis in the mesenchymal cells [12,13,14,15]
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