Journal
CELL
Volume 135, Issue 2, Pages 227-239Publisher
CELL PRESS
DOI: 10.1016/j.cell.2008.09.017
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Funding
- Howard Hughes Medical Institute
- National Institute of Neurological Disorder and Stroke [R01 NS040750]
- National Institute on Aging [R01 AG024945-01]
- University of Michigan (UM) Comprehensive Cancer National Institutes of Health (NIH) [CA46592]
- National Institute of Diabetes, Digestive, and Kidney Diseases [NIH5P60-DK20572]
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Stem cells persist throughout life in diverse tissues by undergoing self-renewing divisions. Self-renewal capacity declines with age, partly because of increasing expression of the tumor suppressor p16(Ink4a). We discovered that the Hmga2 transcriptional regulator is highly expressed in fetal neural stem cells but that expression declines with age. This decrease is partly caused by the increasing expression of let-7b microRNA, which is known to target HMGA2. Hmga2-deficient mice show reduced stem cell numbers and self-renewal throughout the central and peripheral nervous systems of fetal and young-adult mice but not old-adult mice. Furthermore, p16(Ink4a) and p19(Arf) expression were increased in Hmga2-deficient fetal and young-adult stem cells, and deletion of p16(Ink4a) and/or p19(Arf) partially restored self-renewal capacity. let-7b overexpression reduced Hmga2 and increased p16(Ink4a)/p19(Arf) expression. Hmga2 thus promotes fetal and young-adult stem cell self-renewal by decreasing p16(Ink4a)/p19(Arf) expression. Changes in let-7 and Hmga2 expression during aging contribute to the decline in neural stem cell function.
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