Stem cells have an innate ability to occupy their stem cell niche, which in turn, is optimized to house stem cells. Organ aging is associated with reduced stem cell occupancy in the niche, but the mechanisms involved are poorly understood. Here, we report that Notch signaling is increased with age in Drosophila female germline stem cells (GSCs), and this results in their removal from the niche. Clonal analysis revealed that GSCs with low levels of Notch signaling exhibit increased adhesiveness to the niche, thereby out-competing their neighbors with higher levels of Notch; adhesiveness is altered through regulation of E-cadherin expression. Experimental enhancement of Notch signaling in GSCs hastens their age-dependent loss from the niche, and such loss is at least partially mediated by Sex lethal. However, disruption of Notch signaling in GSCs does not delay GSC loss during aging, and nor does it affect BMP signaling, which promotes self-renewal of GSCs. Finally, we show that in contrast to GSCs, Notch activation in the niche (which maintains niche integrity, and thus mediates GSC retention) is reduced with age, indicating that Notch signaling regulates GSC niche occupancy both intrinsically and extrinsically. Our findings expose a novel role of Notch signaling in controlling GSC-niche adhesion in response to aging, and are also of relevance to metastatic cancer cells, in which Notch signaling suppresses cell adhesion.
Aging is frequently associated with a decline in the size of stem cell pools, but little is known regarding the molecular mechanisms underlying this process. Here, we report that Notch signaling is increased in GSCs as they age, and this promotes their removal from the niche in an E-cadherin dependent manner. In contrast to GSCs, niche cells exhibit decreased Notch signaling with age; Notch signaling in these cells controls niche integrity, and consequently GSC retention. While Notch signaling in the niche is regulated by insulin signaling, Notch signaling in GSCs is controlled by Sex lethal, an RNA-binding protein. These results imply that Notch signaling is regulated in a cell-type-dependent manner, and coordination between GSCs and their niche facilitates the removal of cells from the niche during the aging process.