期刊
GENES & DEVELOPMENT
卷 35, 期 3-4, 页码 -出版社
COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT
DOI: 10.1101/gad.339903.120
关键词
Hif1; reactive oxygen species; spermatogonia
资金
- Uehara Memorial Foundation
- Agency for Medical Research and Development [17933225, JP20gm1110008]
- Ministry of Education, Culture, Sports, Science, and Technology [19K22512, 19H05750, 19H04906, 18H04882, 18H05281, 18H02935]
- World Premier International Research Center Initiative (WPI), MEXT, Japan
- Grants-in-Aid for Scientific Research [18H04882, 18H02935, 19H04906, 19K22512, 18H05281] Funding Source: KAKEN
The origin of ROS and oxygen tension play a critical role in driving spermatogonial stem cell (SSC) self-renewal. Under hypoxia, NOX1-derived ROS significantly decrease, impacting the proliferation of SSCs.
Reactive oxygen species (ROS) produced by NADPH1 oxidase 1 (NOX1) are thought to drive spermatogonial stem cell (SSC) self-renewal through feed-forward production of ROS by the ROS-BCL6B-NOX1 pathway. Here we report the critical role of oxygen on ROS-induced self-renewal. Cultured SSCs proliferated poorly and lacked BCL6B expression under hypoxia despite increase in mitochondria-derived ROS. Due to lack of ROS amplification under hypoxia, NOX1-derived ROS were significantly reduced, and Nox1-deficient SSCs proliferated poorly under hypoxia but normally under normoxia. NOX1-derived ROS also influenced hypoxic response in vivo because Nox1-deficient undifferentiated spermatogonia showed significantly reduced expression of HIF1A, a master transcription factor for hypoxic response. Hypoxia-induced poor proliferation occurred despite activation of MYC and suppression of CDKN1A by HIF1A, whose deficiency exacerbated self-renewal efficiency. Impaired proliferation of Nox1or Hif1a-deficient SSCs under hypoxia was rescued by Cdkn1a depletion. Consistent with these observations, Cdkn1a-deficient SSCs proliferated actively only under hypoxia but not under normoxia. On the other hand, chemical suppression of mitochondria-derived ROS or Top1mt mitochondria-specific topoisomerase deficiency did not influence SSC fate, suggesting that NOX1-derived ROS play a more important role in SSCs than mitochondria-derived ROS. These results underscore the importance of ROS origin and oxygen tension on SSC self-renewal.
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