PDF(Pubmed)
Abstract：
Age-related depletion of stem cells causes tissue degeneration and failure to tissue regeneration, driving aging at the organismal level. Previously we reported a cell-non-autonomous DAF-16/FOXO activity in antagonizing the age-related loss of germline stem/progenitor cells (GSPCs) in C. elegans, indicating that regulation of stem cell aging occurs at the organ system level. Here we discover the molecular effector that links the cell-non-autonomous DAF-16/FOXO activity to GSPC maintenance over time by performing a tissue-specific DAF-16/FOXO transcriptome analysis. Our data show that dos-3, which encodes a non-canonical Notch ligand, is a direct transcriptional target of DAF-16/FOXO and mediates the effect of the cell-non-autonomous DAF-16/FOXO activity on GSPC maintenance through activating Notch signaling in the germ line. Importantly, expression of a human homologous protein can functionally substitute for DOS-3 in this scenario. As Notch signaling controls the specification of many tissue stem cells, similar mechanisms may exist in other aging stem cell systems.
摘要：
与年龄相关的干细胞消耗导致组织变性和组织再生失败，在有机体层面驱动衰老。以前，我们报道了一种细胞非自主DAF-16/FOXO活性，可以拮抗秀丽隐杆线虫中与年龄相关的种系干细胞/祖细胞（GSPCs）的损失，表明干细胞衰老的调节发生在器官系统水平。在这里，我们发现了通过进行组织特异性DAF-16/FOXO转录组分析，将细胞非自主DAF-16/FOXO活性与GSPC维持随时间变化的分子效应。我们的数据显示dos-3编码一种非规范Notch配体，是DAF-16/FOXO的直接转录靶标，并通过激活种系中的Notch信号传导来介导细胞非自主DAF-16/FOXO活性对GSPC维持的影响。重要的是,在这种情况下，人同源蛋白的表达可以在功能上替代DOS-3。由于Notch信号控制着许多组织干细胞的规格，类似的机制可能存在于其他老化干细胞系统中。
