Conditional activation of Bmi1 expression regulates self-renewal, apoptosis, and differentiation of neural stem/progenitor cells in vitro and in vivo.
Stem Cells
; 29(4): 700-12, 2011 Apr.
Article
en En
| MEDLINE
| ID: mdl-21305672
ABSTRACT
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.
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Proteínas Represoras
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Proteínas Nucleares
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Diferenciación Celular
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Proteínas Proto-Oncogénicas
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Apoptosis
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Células-Madre Neurales
Tipo de estudio:
Prognostic_studies
Límite:
Animals
Idioma:
En
Revista:
Stem Cells
Año:
2011
Tipo del documento:
Article
País de afiliación:
Reino Unido