Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
Cell Stem Cell. 2012 Nov 2;11(5):676-88. doi: 10.1016/j.stem.2012.07.003.
The role of Notch signaling in the maintenance of adult murine prostate epithelial homeostasis remains unclear. We found that Notch ligands are mainly expressed within the basal cell lineage, while active Notch signaling is detected in both the prostate basal and luminal cell lineages. Disrupting the canonical Notch effector Rbp-j impairs the differentiation of prostate basal stem cells and increases their proliferation in vitro and in vivo, but does not affect luminal cell biology. Conversely, ectopic Notch activation in adult prostates results in a decrease in basal cell number and luminal cell hyperproliferation. TGFβ dominates over Notch signaling and overrides Notch ablation-induced proliferation of prostate basal cells. However, Notch confers sensitivity and positive feedback by upregulating a plethora of TGFβ signaling components including TgfβR1. These findings reveal crucial roles of the self-enforced positive reciprocal regulatory loop between TGFβ and Notch in maintaining prostate basal stem cell dormancy.
Notch 信号通路在维持成年小鼠前列腺上皮细胞内稳态中的作用尚不清楚。我们发现 Notch 配体主要在基底细胞谱系中表达，而活性 Notch 信号通路则在前列腺基底和腔细胞谱系中均被检测到。阻断经典 Notch 效应因子 Rbp-j 会损害前列腺基底干细胞的分化，并增加其在体外和体内的增殖，但不会影响腔细胞的生物学特性。相反，成年前列腺中的异位 Notch 激活会导致基底细胞数量减少和腔细胞过度增殖。TGFβ 信号通路占据主导地位，超过 Notch 信号通路，并逆转 Notch 消融诱导的前列腺基底细胞增殖。然而， Notch 通过上调大量 TGFβ 信号通路成分（包括 TgfβR1）赋予 TGFβ 信号通路敏感性和正反馈。这些发现揭示了 TGFβ 和 Notch 之间自我强化的正反馈调节环在维持前列腺基底干细胞休眠中的关键作用。
