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ROS amplification drives mouse spermatogonial stem cell self-renewal

Research output: Contribution to journalArticle

Hiroko Morimoto, Mito Kanastu-Shinohara, Narumi Ogonuki, Satoshi Kamimura, Atsuo Ogura, Chihiro Yabe-Nishimura, Yoshifumi Mori, Takeshi Morimoto, Satoshi Watanabe, Kinya Otsu, Takuya Yamamoto, Takashi Shinohara

Original languageEnglish
Article numbere201900374
Pages (from-to)e201900374
Number of pages13
JournalLife Science Alliance
Volume2
Issue number2
Early online date2 Apr 2019
DOIs
Publication statusPublished - 2 Apr 2019

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Abstract

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.

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