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

Anna V. Molofsky, Ricardo Pardal, Toshihide Iwashita, In Kyung Park, Michael F. Clarke, Sean J. Morrison

Research output: Contribution to journalArticle

1050 Scopus citations

Abstract

Stem cells persist throughout life by self-renewing in numerous tissues including the central and peripheral 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 defects. 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 p16Ink4ais upregulated in neural stem cells, reducing the rate of proliferation. p16Ink4adeficiency 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 Ink4aexpression 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.

Original languageEnglish (US)
Pages (from-to)962-967
Number of pages6
JournalNature
Volume425
Issue number6961
DOIs
StatePublished - Oct 30 2003

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    Molofsky, A. V., Pardal, R., Iwashita, T., Park, I. K., Clarke, M. F., & Morrison, S. J. (2003). Bmi-1 dependence distinguishes neural stem cell self-renewal from progenitor proliferation. Nature, 425(6961), 962-967. https://doi.org/10.1038/nature02060