@article{8f93fdd3e4f54c6eb05f5fb566b0e37c,
title = "Bmi-1 dependence distinguishes neural stem cell self-renewal from progenitor proliferation",
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.",
author = "Molofsky, {Anna V.} and Ricardo Pardal and Toshihide Iwashita and Park, {In Kyung} and Clarke, {Michael F.} and Morrison, {Sean J.}",
note = "Funding Information: Acknowledgements We thank C. Sigurdson and M. Zabel for critical reading of the manuscript, and R. Zinkernagel for support. This work was supported by grants of the Bundesamt f{\"u}r Bildung und Wissenschaft, the Swiss National Foundation, the NCCR on neural plasticity and repair, and the Migros foundation to A.A. M.P. was a postdoctoral fellow of the Deutsche Forschungsgemeinschaft. M.H. is supported by a generous educational grant of the Catello family and by the Verein zur F{\"o}rderung des Akademischen Nachwuchses. F.L.H. is supported by the Stammbach Foundation and by the Bonizzi-Theler Foundation. Funding Information: Acknowledgements 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 Bmi12/2 mice; and R. DePinho and D. Scadden for the p162/2 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.",
year = "2003",
month = oct,
day = "30",
doi = "10.1038/nature02060",
language = "English (US)",
volume = "425",
pages = "962--967",
journal = "Nature",
issn = "0028-0836",
publisher = "Nature Publishing Group",
number = "6961",
}