RT Journal Article
SR Electronic
T1 ROS amplification drives mouse spermatogonial stem cell self-renewal
JF Life Science Alliance
JO Life Sci. Alliance
FD Life Science Alliance LLC
SP e201900374
DO 10.26508/lsa.201900374
VO 2
IS 2
A1 Hiroko Morimoto
A1 Mito Kanastu-Shinohara
A1 Narumi Ogonuki
A1 Satoshi Kamimura
A1 Atsuo Ogura
A1 Chihiro Yabe-Nishimura
A1 Yoshifumi Mori
A1 Takeshi Morimoto
A1 Satoshi Watanabe
A1 Kinya Otsu
A1 Takuya Yamamoto
A1 Takashi Shinohara
YR 2019
UL https://www.life-science-alliance.org/content/2/2/e201900374.abstract
AB 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.