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 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 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.
Molofsky
Anna V
AV
Howard Hughes Medical Institute, and Departments of Internal Medicine and Cell and Developmental Biology, University of Michigan, Ann Arbor, Michigan 48109-0934, USA.
Pardal
Ricardo
R
Iwashita
Toshihide
T
Park
In-Kyung
IK
Clarke
Michael F
MF
Morrison
Sean J
SJ
D000818:Animals; D017209:Apoptosis; D002454:Cell Differentiation; D002455:Cell Division; D019070:Cell Lineage; D002470:Cell Survival; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009420:Nervous System / Q000166:cytology* / Q000378:metabolism*; D009432:Neural Crest / Q000166:cytology / Q000378:metabolism; D009474:Neurons / Q000166:cytology* / Q000378:metabolism*; D009687:Nuclear Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D063150:Polycomb Repressive Complex 1; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism*
C489421:Bmi1 protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; D063150:Polycomb Repressive Complex 1