title: ROS are required for mouse spermatogonial stem cell self-renewal.
abstract: Reactive oxygen species (ROS) generation is implicated in stem cell self-renewal in several tissues but is thought to be detrimental for spermatogenesis as well as spermatogonial stem cells (SSCs). Using cultured SSCs, we show that ROS are generated via the AKT and MEK signaling pathways under conditions where the growth factors glial cell line-derived neurotrophic factor and fibroblast growth factor 2 drive SSC self-renewal and, instead, stimulate self-renewal at physiological levels. SSCs depleted of ROS stopped proliferating, but they showed enhanced self-renewal when ROS levels were increased by the addition of hydrogen peroxide, which induced the phosphorylation of stress kinases p38 mitogen-activated protein kinase (MAPK) and c-jun N-terminal kinase (JNK). Moreover, ROS depletion in vivo decreased SSC number in the testis, and NADPH oxidase 1 (Nox1)-deficient SSCs exhibited reduced self-renewal division upon serial transplantation. These results suggest that ROS generated by Nox1 play critical roles in SSC self-renewal via the activation of the p38 MAPK and JNK pathways.
authors.affiliation: Department of Molecular Genetics, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Morimoto
authors.forename: Kazumi
authors.initials: K
authors.lastname: Iwata
authors.forename: Narumi
authors.initials: N
authors.lastname: Ogonuki
authors.forename: Kimiko
authors.initials: K
authors.lastname: Inoue
authors.forename: Ogura
authors.initials: O
authors.lastname: Atsuo
authors.forename: Mito
authors.initials: M
authors.lastname: Kanatsu-Shinohara
authors.forename: Takeshi
authors.initials: T
authors.lastname: Morimoto
authors.forename: Chihiro
authors.initials: C
authors.lastname: Yabe-Nishimura
authors.forename: Takashi
authors.initials: T
authors.lastname: Shinohara
mesh_terms: D053687:Adult Stem Cells / Q000166:cytology* / Q000378:metabolism*; D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction; D013093:Spermatogonia / Q000166:cytology* / Q000378:metabolism*
chemical_list: D017382:Reactive Oxygen Species; D051057:Proto-Oncogene Proteins c-akt