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

Sophia W.M. Bruggeman; Merel E. Valk-Lingbeek; Petra P.M. van der Stoop; Jacqueline J.L. Jacobs; Karin Kieboom; Ellen Tanger; Danielle Hulsman; Carly Leung; Yvan Arsenijevic; Silvia Marino; Maarten van Lohuizen

doi:10.1101/gad.1299305

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

¹Division of Molecular Genetics, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands; ²Department of Pathology, Institute of Clinical Pathology, University of Zürich, 8091 Zürich, Switzerland; ³Laboratory of Oculogenetics, Opthalmic Hospital Jules Gonin, Lausanne University, 1004 Lausanne, Switzerland.

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.

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Footnotes

Supplemental material is available at http://www.genesdev.org.
Article and publication are at http://www.genesdev.org/cgi/doi/10.1101/gad.1299305.
^4,5
↵4,5 These authors contributed equally to this work.
⁶
↵6 Corresponding author. E-MAIL m.v.lohuizen{at}nki.nl; FAX 31-20-512-2011.
- Accepted May 4, 2005.
- Received January 19, 2005.
Cold Spring Harbor Laboratory Press