Gli1 Induces G2/M Arrest and Apoptosis in Hippocampal but Not Tumor-Derived Neural Stem Cells
Article first published online: 14 FEB 2008
Copyright © 2008 AlphaMed Press
Volume 26, Issue 4, pages 1027–1036, April 2008
How to Cite
Galvin, K. E., Ye, H., Erstad, D. J., Feddersen, R. and Wetmore, C. (2008), Gli1 Induces G2/M Arrest and Apoptosis in Hippocampal but Not Tumor-Derived Neural Stem Cells. STEM CELLS, 26: 1027–1036. doi: 10.1634/stemcells.2007-0879
- Issue published online: 2 JAN 2009
- Article first published online: 14 FEB 2008
- Manuscript Accepted: 25 JAN 2008
- Manuscript Received: 18 OCT 2007
- Sonic hedgehog;
- Neural stem cells;
- Tumor-derived stem cells;
- Cancer stem cells;
Sonic hedgehog (Shh) is necessary for sustaining the proliferation of neural stem cells (NSCs), yet little is known about its mechanisms. Whereas Gli1, Gli2, and Gli3, the primary mediators of Shh signaling, were all expressed in hippocampal neural progenitors, Shh treatment of NSCs induced only Gli1 expression. Acute depletion of Gli1 in postnatal NSCs by short-hairpin RNA decreased proliferation, whereas germline deletion of Gli1 did not affect NSC proliferation, suggesting a difference in mechanisms of Gli1 compensation that may be developmentally dependent. To determine whether Gli1 was sufficient to enhance NSC proliferation, we overexpressed this mitogen and were surprised to find that Gli1 resulted in decreased proliferation, accumulation of NSCs in the G2/M phase of cell cycle, and apoptosis. In contrast, Gli1-expressing lineage-restricted neural precursors demonstrated a 4.5-fold proliferation enhancement. Expression analyses of Gli1-expressing NSCs identified significant induction of Gadd45a and decreased cyclin A2 and Stag1 mRNA, genes involved in the G2-M transition and apoptosis. Furthermore, Gadd45a overexpression was sufficient to partially recapitulate the Gli1-induced G2/M accumulation and cell death of NSCs. In contrast to normal stem cells, tumor-derived stem cells had markedly higher basal Gli1 expression and did not undergo apoptosis with further elevation of Gli1. Our data suggest that Gli1-induced apoptosis may serve as a protective mechanism against premature mitosis and may give insight into mechanisms by which nonmalignant stem cells restrain hyperproliferation in the context of potentially transforming mitogenic signals. Tumor-derived stem cells apparently lack these mechanisms, which may contribute to their unrestrained proliferation and malignant potential.
Disclosure of potential conflicts of interest is found at the end of this article.