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.