Journal
STEM CELLS
Volume 29, Issue 4, Pages 700-712Publisher
WILEY
DOI: 10.1002/stem.614
Keywords
Bmi1; Neural stem cells; Self-renewal; Neuronal differentiation; Survivin; Brain tumors
Categories
Funding
- Oncosuisse [OCS01636-02-2005]
- Cancer Research UK [C23985/A7802]
- Medical Research Council UK [G0800020, 85704]
- MRC [G0802546, G0800020] Funding Source: UKRI
- Medical Research Council [G0802546, G0800020] Funding Source: researchfish
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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
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