Letters to Nature

Nature 425, 962-967 (30 October 2003) | doi:10.1038/nature02060; Received 28 March 2003; Accepted 1 September 2003; Published online 22 October 2003

Bmi-1 dependence distinguishes neural stem cell self-renewal from progenitor proliferation

Anna V. Molofsky1,2, Ricardo Pardal1,2, Toshihide Iwashita1, In-Kyung Park, Michael F. Clarke1 & Sean J. Morrison1

  1. Howard Hughes Medical Institute, and Departments of Internal Medicine and Cell and Developmental Biology, University of Michigan, Ann Arbor, Michigan 48109-0934, USA
  2. These authors contributed equally to this work

Correspondence to: Sean J. Morrison1 Email: seanjm@umich.edu
The microarray data entitled "Neurospheres of WT and BMI-1 KO" has been deposited in the GEO (Gene Expression Omnibus) database under accession number GSE611.

Stem cells persist throughout life by self-renewing in numerous tissues including the central1 and peripheral2 nervous systems. This raises the issue of whether there is a conserved mechanism to effect self-renewing divisions. Deficiency in the polycomb family transcriptional repressor Bmi-1 leads to progressive postnatal growth retardation and neurological defects3. Here we show that Bmi-1 is required for the self-renewal of stem cells in the peripheral and central nervous systems but not for their survival or differentiation. The reduced self-renewal of Bmi-1-deficient neural stem cells leads to their postnatal depletion. In the absence of Bmi-1, the cyclin-dependent kinase inhibitor gene p16 Ink4a is upregulated in neural stem cells, reducing the rate of proliferation. p16 Ink4a deficiency partially reverses the self-renewal defect in Bmi-1 -/- neural stem cells. This conserved requirement for Bmi-1 to promote self-renewal and to repress p16 Ink4a expression suggests that a common mechanism regulates the self-renewal and postnatal persistence of diverse types of stem cell. Restricted neural progenitors from the gut and forebrain proliferate normally in the absence of Bmi-1. Thus, Bmi-1 dependence distinguishes stem cell self-renewal from restricted progenitor proliferation in these tissues.