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Tissue-Specific Stem Cells
Article first published online: 5 APR 2011
Copyright © 2011 AlphaMed Press
Volume 29, Issue 4, pages 700–712, April 2011
How to Cite
Yadirgi, G., Leinster, V., Acquati, S., Bhagat, H., Shakhova, O. and Marino, S. (2011), Conditional Activation of Bmi1 Expression Regulates Self-renewal, Apoptosis, and Differentiation of Neural Stem/Progenitor Cells In Vitro and In Vivo. STEM CELLS, 29: 700–712. doi: 10.1002/stem.614
Disclosure of potential conflicts of interest is found at the end of this article.
Author contributions: G.Y., V.L., and S.A.: collection and/or assembly of data, data analysis and interpretation, manuscript writing; H.B.: collection and/or assembly of data; O.S.: conception and design, collection and/or assembly of data, data analysis and interpretation; S.M.: conception and design, data analysis and interpretation, financial support, manuscript writing. G.Y. and V.L. contributed equally to this work.
First published online in STEM CELLSEXPRESS February 8, 2011.
- Issue published online: 5 APR 2011
- Article first published online: 5 APR 2011
- Accepted manuscript online: 8 FEB 2011 03:45PM EST
- Manuscript Accepted: 21 JAN 2011
- Manuscript Received: 26 AUG 2010
- Oncosuisse. Grant Number: OCS01636-02-2005
- Cancer Research UK. Grant Number: C23985/A7802
- Medical Research Council UK. Grant Numbers: G0800020, 85704
- Neural stem cells;
- Neuronal differentiation;
- Brain tumors
The Polycomb group protein Bmi1 is a key regulator of self-renewal of embryonic and adult central nervous system stem cells, and its overexpression has been shown to occur in several types of brain tumors. In a Cre/LoxP-based conditional transgenic mouse model, we show that fine-tuning of Bmi1 expression in embryonic neural stem cell (NSC) is sufficient to increase their proliferation and self-renewal potential both in vitro and in vivo. This is linked to downregulation of both the ink4a/ARF and the p21/Foxg1 axes. However, increased and ectopic proliferation induced by overexpression of Bmi1 in progenitors committed toward a neuronal lineage during embryonic cortical development, triggers apoptosis through a survivin-mediated mechanism and leads to reduced brain size. Postnatally, however, increased self-renewal capacity of neural stem/progenitor cells (NSPC) is independent of Foxg1 and resistance to apoptosis is observed in neural progenitors derived from NSC-overexpressing Bmi1. Neoplastic transformation is absent in mice-overexpressing Bmi1 aged up to 20 months. These studies provide strong evidence that fine tuning of Bmi1 expression is a viable tool to increase self-renewal capacity of NSCs both in vitro and in vivo without eliciting neoplastic transformation of these cells. STEM Cells 2011;29:700–712