Ink4a and Arf differentially affect cell proliferation and neural stem cell self-renewal in Bmi1-deficient mice

Abstract

The Polycomb group (PcG) gene Bmi1 promotes cell proliferation and stem cell self-renewal by repressing the Ink4a/Arf locus. We used a genetic approach to investigate whether Ink4a or Arf is more critical for relaying Bmi1 function in lymphoid cells, neural progenitors, and neural stem cells. We show that Arf is a general target of Bmi1, however particularly in neural stem cells, derepression of Ink4a contributes to Bmi1 −/− phenotypes. Additionally, we demonstrate haploinsufficient effects for the Ink4a/Arf locus downstream of Bmi1 in vivo. This suggests differential, cell type-specific roles for Ink4a versus Arf in PcG-mediated (stem) cell cycle control.Supplemental material is available at http://www.genesdev.org.

Epigenetic regulation of aging stem cells

“…Deletion of the entire p16 INK4a /p19 ARF locus, but not that of p19 ARF alone, can mostly rescue the effect of Bmi1 deficiency on HSC self-renewal in long-term competitive repopulation assays (Oguro et al, 2006). p19 ARF may be a more critical target in adult NSCs, as p19 ARF deletion partially rescues self-renewal defects caused by Bmi1 deficiency, although to a lesser extent than deletion of the entire p16 INK4a / p19 ARF locus (Bruggeman et al, 2005;Molofsky et al, 2005). In contrast to chronic Bmi1 loss, acute RNA interference-mediated knockdown of Bmi1 in NSC cultures from young adult mice does not lead to an increase in p16 INK4a or p19 ARF expression, but results in altered expression of another cell cycle inhibitor, p21 CIP1 , which can rescue the antiproliferative phenotype of Bmi1 knockdown (Fasano et al, 2007).…”

“…Furthermore, BMI1 plays a non-cell autonomous role in the bone marrow microenvironment that does not depend on p16 INK4a or p19 ARF (Oguro et al, 2006). Similarly, deletion of the entire p16 INK4a /p19 ARF locus in Bmi1 À/À mice does not completely rescue NSC defects in selfrenewal capacity (Bruggeman et al, 2005;Molofsky et al, 2005).…”

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

“…However, concomitant deletion/suppression of p16 Ink4a or p19 ARF or both does not completely rescue the above-mentioned defects in self-renewal of NSC and proliferation of granule cell progenitors derived from Bmi1À/À mice [8,9]. Another cell cycle inhibitor, namely p21 WAF1/Cip1 , contributes to mediating Bmi1 function in both developmental contexts [10,11].…”

Loss of the human polycomb group protein BMI1 promotes cancer-specific cell death

“…Such developmental abnormalities may be linked to a putative stem cell factor function of Bmi1 (Molofsky et al, 2003;Park et al, 2003;Shakhova et al, 2005), and therefore the loss of Bmi1 could lead to an exhaustion of tissue stem cells that compromises tissue growth. Furthermore, BMI11 is also implicated to sustain both self-renewal and proliferation of neural stem cells by repressing the function of Ink4a-Arf that can lead to growth arrest and premature senescence (Jacobs et al, 1999a;Bruggeman et al, 2005;Molofsky et al, 2005).…”

“…This may be linked to the INK4A-ARF locus, which plays a major role in the regulation of cell proliferation via its p16 and p14 products (Jacobs et al, 1999a;Itahana et al, 2003;Bruggeman et al, 2005;Molofsky et al, 2005;Mihara et al, 2006). As BMI1 acts as a negative regulator of the INK4A-ARF locus, overexpression of BMI1 can repress p16 expression, and thus lead to an immortalization of murine fibroblasts and postpone cellular senescence in normal human cells (Jacobs et al, 1999a;Dimri et al, 2002;Takeda et al, 2004;Mori et al, 2005;Terai et al, 2005).…”