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.

Abstract

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.