Department of Molecular Genetics, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Japan Agency for Medical Research and Development-Core Research for Evolutional Science, Tokyo, Japan.
Life Sci Alliance. 2019 Apr 2;2(2). doi: 10.26508/lsa.201900374. Print 2019 Apr.
Reactive oxygen species (ROS) play critical roles in self-renewal division for various stem cell types. However, it remains unclear how ROS signals are integrated with self-renewal machinery. Here, we report that the MAPK14/MAPK7/BCL6B pathway creates a positive feedback loop to drive spermatogonial stem cell (SSC) self-renewal via ROS amplification. The activation of MAPK14 induced MAPK7 phosphorylation in cultured SSCs, and targeted deletion of or resulted in significant SSC deficiency after spermatogonial transplantation. The activation of this signaling pathway not only induced but also increased ROS levels. Chemical screening of MAPK7 targets revealed many ROS-dependent spermatogonial transcription factors, of which BCL6B was found to initiate ROS production by increasing expression via ETV5-induced nuclear translocation. Because hydrogen peroxide or transfection also induced BCL6B nuclear translocation, our results suggest that BCL6B initiates and amplifies ROS signals to activate ROS-dependent spermatogonial transcription factors by forming a positive feedback loop.
活性氧 (ROS) 在各种干细胞类型的自我更新分裂中发挥着关键作用。然而，ROS 信号如何与自我更新机制整合仍不清楚。在这里，我们报告 MAPK14/MAPK7/BCL6B 途径通过 ROS 放大创建正反馈环以驱动精原干细胞 (SSC) 的自我更新。MAPK14 的激活诱导培养的 SSCs 中 MAPK7 的磷酸化，而 或 的靶向缺失导致精原细胞移植后 SSC 明显缺乏。该信号通路的激活不仅诱导了 BCL6B 的表达，还增加了 ROS 水平。MAPK7 靶标的化学筛选揭示了许多 ROS 依赖性精原细胞转录因子，其中 BCL6B 通过增加 ETV5 诱导的核转位来增加 的表达来启动 ROS 产生。由于过氧化氢或 转染也诱导 BCL6B 核转位，我们的结果表明 BCL6B 通过形成正反馈环来启动和放大 ROS 信号，以激活 ROS 依赖性精原细胞转录因子。
