title: Conditional activation of Bmi1 expression regulates self-renewal, apoptosis, and differentiation of neural stem/progenitor cells in vitro and in vivo.
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.
authors.affiliation: Blizard Institute of Cell and Molecular Science, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom.
authors.forename: Gokhan
authors.initials: G
authors.lastname: Yadirgi
authors.forename: Veronica
authors.initials: V
authors.lastname: Leinster
authors.forename: Serena
authors.initials: S
authors.lastname: Acquati
authors.forename: Heeta
authors.initials: H
authors.lastname: Bhagat
authors.forename: Olga
authors.initials: O
authors.lastname: Shakhova
authors.forename: Silvia
authors.initials: S
authors.lastname: Marino
mesh_terms: D051698:Activating Transcription Factor 2 / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D002454:Cell Differentiation; D002478:Cells, Cultured; D002490:Central Nervous System / Q000196:embryology; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics; D051858:Forkhead Transcription Factors / Q000235:genetics; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics; D058953:Neural Stem Cells / Q000166:cytology / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D063150:Polycomb Repressive Complex 1; D063146:Polycomb-Group Proteins; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D000077022:Survivin; D025803:Tumor Suppressor Protein p14ARF / Q000235:genetics
chemical_list: D051698:Activating Transcription Factor 2; C497106:Atf2 protein, mouse; C117749:Birc5 protein, mouse; C489421:Bmi1 protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050759:Cyclin-Dependent Kinase Inhibitor p21; D051858:Forkhead Transcription Factors; C489565:Foxg1 protein, mouse; D051034:Inhibitor of Apoptosis Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D063146:Polycomb-Group Proteins; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; D000077022:Survivin; D025803:Tumor Suppressor Protein p14ARF; D063150:Polycomb Repressive Complex 1