| The mammalian brain is formed from a pool of heterogeneous, dynamic neural progenitor cells. These neural progenitor cells change their proliferative potential and cell-lineage potency throughout development. Bmi-1 is a Polycomb group gene known to be involved in the post-natal maintenance of neural progenitor cell proliferation. We sought to determine if neural progenitors respond differently to loss of Bmi-1 at different developmental stages. Using lentiviral mediated RNA interference, we observed a progressive increase in the dependence on Bmi-1 for neural progenitor cell proliferation. Our results indicate that acute knock-down of Bmi-1 results in a phenotype more severe than that observed in the Bmi-1 null animal, and that this phenotype is independent of increased expression from the Ink4a locus.; Having demonstrated that loss of Bmi-1 results in impaired neural progenitor cell activity, we sought to determine the effect of enforced expression of Bmi-1. Neural progenitor cells isolated from embryonic or adult brains show increased proliferative potential after enforced expression of Bmi-1. The resulting neural colonies remain multilineage, comprised of neurons, oligodendrocytes, and astrocytes. Moreover, enforced expression of Bmi-1 in adult neural progenitors results in enhanced neuropotency. Together these studies demonstrate that Bmi-1 is necessary and sufficient for neural stem and progenitor cell self renewal.; We have conducted genome-wide transcriptional analyses to generate annotated gene lists of putative Bmi-1 self renewal effectors. Bmi-1 over-expression is found in diverse cancers; however, over-expression of Bmi-1 in neural progenitor cells results in a coordinated increase in proliferation and differentiation potential. Molecular mechanisms employed in this coordinated response to Bmi-1 might be lacking in transformed cells. Examination of candidate down-stream Bmi-1 effectors uncovered in this study may provide mechanistic insight into stem and cancerous cell function. |
