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.

Analysis of GPI-anchored proteins involved in germline stem cell proliferation in the Caenorhabditis elegans germline stem cell niche

Stem cells divide and undergo self-renewal depending on the signals received from the stem cell niche. This phenomenon is indispensable to maintain tissues and organs in individuals. However, not all the molecular factors and mechanisms of self-renewal are known. In our previous study, we reported that glycosylphosphatidylinositol (GPI)-anchored proteins (GPI-APs) synthesized in the distal tip cells (DTCs; the stem cell niche) are essential for germline stem cell proliferation in Caenorhabditis elegans. Here, we characterized the GPI-APs required for proliferation. We selected and verified the candidate GPI-APs synthesized in DTCs by RNA interference screening and found that F57F4.3 (GFI-1), F57F4.4 and F54E2.1 are necessary for germline proliferation. These proteins are likely involved in the same pathway for proliferation and activated by the transcription factor PQM-1. We further provided evidence suggesting that these GPI-APs act through fatty acid remodelling of the GPI anchor, which is essential for association with lipid rafts. These findings demonstrated that GPI-APs, particularly F57F4.3/4 and F54E2.1, synthesized in the germline stem cell niche are located in lipid rafts and involved in promoting germline stem cell proliferation in C. elegans. The findings may thus shed light on the mechanisms by which GPI-APs regulate stem cell self-renewal.

microRNAs selectively protect hub cells of the germline stem cell niche from apoptosis

Genotoxic stress such as irradiation causes a temporary halt in tissue regeneration. The ability to regain regeneration depends on the type of cells that survived the assault. Previous studies showed that this propensity is usually held by the tissue-specific stem cells. However, stem cells cannot maintain their unique properties without the support of their surrounding niche cells. In this study, we show that exposure of Drosophila melanogaster to extremely high levels of irradiation temporarily arrests spermatogenesis and kills half of the stem cells. In marked contrast, the hub cells that constitute a major component of the niche remain completely intact. We further show that this atypical resistance to cell death relies on the expression of certain antiapoptotic microRNAs (miRNAs) that are selectively expressed in the hub and keep the cells inert to apoptotic stress signals. We propose that at the tissue level, protection of a specific group of niche cells from apoptosis underlies ongoing stem cell turnover and tissue regeneration.