ROS amplification drives mouse spermatogonial stem cell self-renewal
ROS amplification drives mouse spermatogonial stem cell self-renewal
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DOI：
10.26508/lsa.201900374
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发表时间：
2019-04-01
影响因子：
4.4
通讯作者：
Shinohara, Takashi
中科院分区：
文献类型：
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作者：
Morimoto, Hiroko;Kanastu-Shinohara, Mito;Shinohara, Takashi
活性氧（ROS）在各种干细胞类型的自我更新分裂中起着至关重要的作用。然而，目前尚不清楚ROS信号如何与自我更新机制相结合。在这里，我们报道了MAPK14/MAPK7/BCL6B通路通过ROS扩增创建一个正反馈回路来驱动精原干细胞（SSC）自我更新。MAPK14的激活在培养的SSC中诱导MAPK7磷酸化，而MAPK14或MAPK7的靶向缺失导致精原移植后SSC明显缺失。该信号通路的激活不仅诱导了Nox1，还增加了ROS水平。对MAPK7靶点的化学筛选发现了许多ROS依赖的精原转录因子，其中BCL6B通过etv5诱导的核易位增加Nox1的表达，从而启动ROS的产生。由于过氧化氢或Nox1转染也会诱导BCL6B核易位，我们的研究结果表明，BCL6B启动并放大ROS信号，通过形成一个正反馈回路来激活ROS依赖性精原细胞转录因子。
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 Mapk14 or Mapk7 resulted in significant SSC deficiency after spermatogonial transplantation. The activation of this signaling pathway not only induced Nox1 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 Nox1 expression via ETV5-induced nuclear translocation. Because hydrogen peroxide or Nox1 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.