Hmga2 Promotes Neural Stem Cell Self-Renewal in Young but Not Old Mice by Reducing p16Ink4a and p19Arf Expression

Abstract

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 p16Ink4a. 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, p16Ink4a and p19Arf expression were increased in Hmga2-deficient fetal and young-adult stem cells, and deletion of p16Ink4a and/or p19Arf partially restored self-renewal capacity. let-7b overexpression reduced Hmga2 and increased p16Ink4a/p19Arf expression. Hmga2 thus promotes fetal and young-adult stem cell self-renewal by decreasing p16Ink4a/p19Arf expression. Changes in let-7 and Hmga2 expression during aging contribute to the decline in neural stem cell function. © 2008 Elsevier Inc. All rights reserved.