YAP/Yorkie in the germline modulates the age-related decline of germline stem cells and niche cells

The properties and behaviour of stem cells rely heavily on signaling from the local microenvironment. At the apical end of Drosophila testis, self-renewal and differentiation of germline stem cells (GSCs) are tightly controlled by distinct somatic cells that comprise a specialised stem cell niche known as the hub. The hub maintains GSC homeostasis through adhesion and cell signaling. The Salvador/Warts/Hippo (SWH) pathway, which suppresses the transcriptional co-activator YAP/Yki via a kinase cascade, is a known regulator of stem cell proliferation and differentiation. Here, we show that increasing YAP/Yki expression in the germline, as well as reducing Warts levels, blocks the decrease of GSC numbers observed in aging flies, with only a small increase on their proliferation. An increased expression of YAP/Yki in the germline or a reduction in Warts levels also stymies an age-related reduction in hub cell number, suggesting a bilateral relationship between GSCs and the hub. Conversely, RNAi-based knockdown of YAP/Yki in the germline leads to a significant drop in hub cell number, further suggesting the existence of such a SC-to-niche relationship. All together, our data implicate the SWH pathway in Drosophila GSC maintenance and raise questions about its role in stem cell homeostasis in aging organisms.

干细胞的特性与行为极大程度上依赖于局部微环境的信号调控。在果蝇（Drosophila）睾丸的顶端区域，生殖系干细胞（germline stem cells, GSCs）的自我更新与分化，由构成特化干细胞微环境（stem cell niche）的不同体细胞严格管控，该微环境被称为集线器（hub）。集线器通过细胞黏附与细胞信号传导维持GSC的稳态。Salvador/Warts/Hippo（SWH）信号通路可通过激酶级联反应抑制转录共激活因子YAP/Yki，是已知的干细胞增殖与分化调控因子。本研究发现，在生殖系中上调YAP/Yki的表达，以及降低Warts的表达水平，可阻断衰老果蝇中观察到的GSC数量下降现象，仅对其增殖能力造成小幅提升。在生殖系中上调YAP/Yki的表达，或降低Warts的表达水平，同样会延缓集线器细胞数量随年龄增长而减少的趋势，这表明GSC与集线器之间存在双向调控关系。反之，在生殖系中通过RNA干扰（RNAi）敲低YAP/Yki的表达，会导致集线器细胞数量显著下降，进一步证实了干细胞至微环境的这种调控关系的存在。综上，本研究的数据表明SWH信号通路参与果蝇GSC的维持，并为其在衰老生物体的干细胞稳态调控中的作用提出了新的研究问题。