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


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 p16Ink4a is upregulated in neural stem cells, reducing the rate of proliferation. p16Ink4a 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 p16Ink4a 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.

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Figure 1: CNS stem cells and gut neural crest stem cells (NCSCs) require Bmi-1 to self-renew normally.
Figure 2: Bmi-1 deficiency reduces proliferation but does not increase cell death in CNS stem cell colonies. P0 SVZ cells were dissociated and plated in adherent cultures, and the number of cells per colony was counted after 4, 7 and 14 d (a).
Figure 3: p16Ink4a negatively regulates the self-renewal of CNS stem cells and gut NCSCs in culture.
Figure 4: Restricted neural progenitors from the CNS and PNS proliferate normally in the absence of Bmi-1. E14 telencephalon cells or P0 or P30 SVZ cells were dissociated and cultured at clonal density under adherent conditions.

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We thank M. Kukuruga, A. M. Deslaurier, M. Kiel and the University of Michigan Flow-Cytometry Core Facility (supported by University of Michigan Comprehensive Cancer and Multipurpose Arthritis Center NIH grants); D. Qian for mouse breeding; D. Misek, R. Koenig and R. Kuick for microarray analysis; E. Smith in the Hybridoma Core Facility (supported through the Michigan Diabetes Research and Training Center, and the Rheumatic Disease Center); M. van Lohuizen for the Bmi1-/- mice; and R. DePinho and D. Scadden for the p16-/- mice. This work was supported by the NIH, the Searle Scholars Program and the Howard Hughes Medical Institute. A.V.M. was supported by a University of Michigan MSTP training grant. R.P. was the recipient of a postdoctoral fellowship from the Spanish Ministry of Science and Technology.

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Correspondence to Sean J. Morrison.

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Molofsky, A., Pardal, R., Iwashita, T. et al. Bmi-1 dependence distinguishes neural stem cell self-renewal from progenitor proliferation. Nature 425, 962–967 (2003).

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