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Tissue-Specific Stem Cells
Article first published online: 22 OCT 2012
Copyright © 2012 AlphaMed Press
Volume 30, Issue 11, pages 2535–2547, November 2012
How to Cite
Hou, Y., Ouyang, X., Wan, R., Cheng, H., Mattson, M. P. and Cheng, A. (2012), Mitochondrial Superoxide Production Negatively Regulates Neural Progenitor Proliferation and Cerebral Cortical Development. STEM CELLS, 30: 2535–2547. doi: 10.1002/stem.1213
Author contributions: Y.H., M.P.M., and A.C.: designed the study; Y.H., X.O., R.W., and A.C.: performed the experiments; Y.H. and A.C.: analyzed the data; H.C.: contributed reagents; Y.H, H.C., M.P.M., and A.C.: wrote the manuscript.
Disclosure of potential conflicts of interest is found at the end of this article.
First published online in STEM CELLSEXPRESS September 4, 2012.
- Issue published online: 22 OCT 2012
- Article first published online: 22 OCT 2012
- Accepted manuscript online: 4 SEP 2012 10:02AM EST
- Manuscript Accepted: 25 JUL 2012
- Manuscript Received: 9 APR 2012
- Intramural Research Program of the National Institute on Aging
- National Natural Science Foundation
- National Basic Research Program of China. Grant Number: 2011CB809100
- Manganese superoxide dismutase;
- Extracellular signal-regulated kinases;
- Mitochondrial permeability transition pore;
- Neural progenitor cells;
Although high amounts of reactive oxygen species (ROS) can damage cells, ROS can also play roles as second messengers, regulating diverse cellular processes. Here, we report that embryonic mouse cerebral cortical neural progenitor cells (NPCs) exhibit intermittent spontaneous bursts of mitochondrial superoxide (SO) generation (mitochondrial SO flashes) that require transient opening of membrane permeability transition pores (mPTP). This quantal SO production negatively regulates NPC self-renewal. Mitochondrial SO scavengers and mPTP inhibitors reduce SO flash frequency and enhance NPC proliferation, whereas prolonged mPTP opening and SO generation increase SO flash incidence and decrease NPC proliferation. The inhibition of NPC proliferation by mitochondrial SO involves suppression of extracellular signal-regulated kinases. Moreover, mice lacking SOD2 (SOD2−/− mice) exhibit significantly fewer proliferative NPCs and differentiated neurons in the embryonic cerebral cortex at midgestation compared with wild-type littermates. Cultured SOD2−/− NPCs exhibit a significant increase in SO flash frequency and reduced NPC proliferation. Taken together, our findings suggest that mitochondrial SO flashes negatively regulate NPC self-renewal in the developing cerebral cortex. STEM CELLS2012;30:2535–2547