Conditional Activation of Bmi1 Expression Regulates Self-renewal, Apoptosis, and Differentiation of Neural Stem/Progenitor Cells In Vitro and In Vivo§

Authors

  • Gokhan Yadirgi,

    1. Blizard Institute of Cell and Molecular Science, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
    Search for more papers by this author
  • Veronica Leinster,

    1. Blizard Institute of Cell and Molecular Science, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
    Search for more papers by this author
  • Serena Acquati,

    1. Blizard Institute of Cell and Molecular Science, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
    Search for more papers by this author
  • Heeta Bhagat,

    1. Blizard Institute of Cell and Molecular Science, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
    Search for more papers by this author
  • Olga Shakhova,

    1. Blizard Institute of Cell and Molecular Science, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
    Search for more papers by this author
  • Silvia Marino

    Corresponding author
    1. Blizard Institute of Cell and Molecular Science, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
    • Blizard Institute of Cell and Molecular Science, 4 Newark Street, London E1 2AT, United Kingdom
    Search for more papers by this author
    • Ph: 44-207-882-2585; Fax: 44-207-882-2180


  • 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.

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. STEM Cells 2011;29:700–712

Ancillary