title: Notch signaling mediates the age-associated decrease in adhesion of germline stem cells to the niche.
abstract: 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.
authors.affiliation: Institute of Cellular and Organismic Biology, Academia Sinica, Taipei, Taiwan; Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan.
authors.forename: Chen-Yuan
authors.initials: CY
authors.lastname: Tseng
authors.affiliation: Institute of Cellular and Organismic Biology, Academia Sinica, Taipei, Taiwan.
authors.forename: Shih-Han
authors.initials: SH
authors.lastname: Kao
authors.affiliation: Institute of Cellular and Organismic Biology, Academia Sinica, Taipei, Taiwan.
authors.forename: Chih-Ling
authors.initials: CL
authors.lastname: Wan
authors.affiliation: Institute of Cellular and Organismic Biology, Academia Sinica, Taipei, Taiwan.
authors.forename: Yueh
authors.initials: Y
authors.lastname: Cho
authors.affiliation: Genomic Core Facility, Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan.
authors.forename: Shu-Yun
authors.initials: SY
authors.lastname: Tung
authors.affiliation: Institute of Cellular and Organismic Biology, Academia Sinica, Taipei, Taiwan.
authors.forename: Hwei-Jan
authors.initials: HJ
authors.lastname: Hsu
mesh_terms: D000375:Aging; D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000502:physiology; D064200:Cdh1 Proteins / Q000378:metabolism; D002448:Cell Adhesion; D049109:Cell Proliferation; D029721:Drosophila Proteins / Q000378:metabolism / Q000502:physiology*; D004331:Drosophila melanogaster / Q000166:cytology; D005260:Female; D016601:RNA-Binding Proteins / Q000502:physiology; D051880:Receptors, Notch / Q000502:physiology*; D015398:Signal Transduction; D055153:Stem Cell Niche; D013234:Stem Cells / Q000502:physiology*
chemical_list: D019485:Bone Morphogenetic Proteins; D064200:Cdh1 Proteins; D029721:Drosophila Proteins; C497759:N protein, Drosophila; D016601:RNA-Binding Proteins; D051880:Receptors, Notch; C067777:Sxl protein, Drosophila; C577674:fzr protein, Drosophila