Conditional activation of Bmi1 in embryonic and postnatal neural stem/progenitor cells in mouse models: analysis of its effect on their biological properties and tumourigenesis

Abstract

The Polycomb group protein Bmi1 is a key transcriptional regulator of self renewal of embryonic and adult neural stem and progenitor cells (NSPC) and its over-expression has been shown to occur in several types of brain tumour. In a Cre/LoxP-based conditional transgenic mouse model we show that fine-tuning of Bmi1 expression in embryonic NSPC is sufficient to increase their proliferation and self renewal potential in vitro. This is linked to downregulation of both the ink4a/ARF and the p21/Foxg1 axes. However, sustained over-expression of Bmi1 in differentiating progenitor cells leads to increased apoptosis of neuronal progenitor cells. Moreover, neurospheres derived from Bmi1 over-expressing NSPC contain more cells positive for glial markers such as NG2 and A2B5. Postnatally, however, increased self renewal capacity of NSPC is independent of Foxg1 and resistance to apoptosis is observed in neural progenitors derived from NSPC over-expressing Bmi1. No neoplastic transformation is seen in mice over-expressing Bmi1 in the SVZ stem cell compartment of transgenic mice (NestinCre;STOPFloxBmi1) aged up to 20 months. These studies provide strong evidence that fine tuning of Bmi1 ex-pression is a viable tool to increase self renewal capacity of neural stem cells in vi-tro and that it does not elicit neoplastic transformation of these cells. However, activation of Bmi1 over-expression in the postnatal SVZ concomitantly with inacti-vation of p53, a common predisposing mutation to glial tumour development, leads to formation of low grade glioma in these mice. These data raise the possibil-ity that genetic collaboration between Bmi1 and p53 may be a key event in the pathogenesis of low grade glial tumours.