Bmi-1 promotes neural stem cell self-renewal and neural development but not mouse growth and survival by repressing the p16Ink4a and p19Arf senescence pathways.

By A. Molofsky, Shenghui He, Mohammad Bydon, S. Morrison, R. Pardal. Genes & Development, 2005

658 citations recorded by the source corpus.

Bmi-1 is required for the post-natal maintenance of stem cells in multiple tissues including the central nervous system (CNS) and peripheral nervous system (PNS). Deletion of Ink4a or Arf from Bmi-1(-/-) mice partially rescued stem cell self-renewal and stem cell frequency in the CNS and PNS, as well as forebrain proliferation and gut neurogenesis. Arf deficiency, but not Ink4a deficiency, partially rescued cerebellum development, demonstrating regional differences in the sensitivity of progenitors to p16Ink4a and p19Arf. Deletion of both Ink4a and Arf did not affect the growth or survival of Bmi-1(-/-) mice or completely rescue neural development. Bmi-1 thus prevents the premature senescence of neural stem cells by repressing Ink4a and Arf, but additional pathways must also function downstream of Bmi-1.

Subfields: Developmental Neuroscience, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/91b70baadc83b95d8bfe6d99985b59f8310c4737

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Citations in the corpus

Hedgehog signaling and Bmi-1 regulate self-renewal of normal and malignant human mammary stem cells. (2006, background): “These studies have recently been confirmed and extended using mouse knockout models of INK-4A and p19 ARF (31).”
Polycomb group proteins: multi-faceted regulators of somatic stem cells and cancer. (2010, positive): “Somatic Ezh2 mutations and deletions were found in 22% of germinal center diffuse large B cell lymphomas, 7% follicular lymphomas, and 12%–23% of patients with myelodysplasic and myeloproliferative disorders (Ernst et al., 2010; Morin et al., 2010; Nikoloski et al., 2010).”
Senescence impairs successful reprogramming to pluripotent stem cells. (2009, background): “BMI1 has been shown to regulate cellular senescence in murine and human cells (Itahana et al., 2003; Jacobs et al., 1999) and is also thought to prevent premature senescence of adult stem cells by repressing the INK4b-ARF-INK4a locus (Bruggeman et al., 2005; Molofsky et al., 2005).”
Mechanisms of stem cell self-renewal. (2009, background): “Bmi-1 also promotes neural stem cell self-renewal by repressing the expression of p16Ink4a and p19Arf (Bruggeman et al. 2005; Molofsky et al. 2003, 2005); however, Bmi-1 is not required in vivo during fetal development to repress p16Ink4a and p19Arf, rather it is required throughout adulthood.”
Ezh2 Orchestrates Gene Expression for the Stepwise Differentiation of Tissue-Specific Stem Cells (2009, background): “Ironically, Bmi1 mutants malfunction in maintaining hematopoietic and neuronal adult SC renewal, in part due to misregulation of the Ink4A/Arf locus (Bruggeman et al., 2005; Molofsky et al., 2003, 2005; Park et al., 2003).”
The Polycomb group proteins bind throughout the INK4A-ARF locus and are disassociated in senescent cells. (2007, background): “2004), and this has primarily been attributed to its ability to repress the Ink4a-Arf locus (Bruggeman et al. 2005; Molofsky et al. 2005).”
Down-regulation of miRNA-200c Links Breast Cancer Stem Cells with Normal Stem Cells (2009, background): “…critically conserved nucleotides indicative of a legitimate target and is known to be essential in regulating selfrenewal and differentiation of other stem cell types, including hematopoietic, brain, and mammary stem cells (Molofsky et al., 2005; Park et al., 2003; Pietersen et al., 2008).”
Role of Bmi-1 and Ring1A in H2A ubiquitylation and Hox gene silencing. (2005, background): “In addition to regulating Hox gene expression, Bmi-1 is known to regulate Ink4a and ARF (Jacobs et al., 1999b; Molofsky et al., 2005), two important cell cycle regulators.”