Gli1 induces G2/M arrest and apoptosis in hippocampal but not tumor-derived neural stem cells
Gli1 induces G2/M arrest and apoptosis in hippocampal but not tumor-derived neural stem cells
复制标题
DOI：
10.1634/stemcells.2007-0879
复制
发表时间：
2008-04-01
期刊：
影响因子：
5.2
通讯作者：
Wetmore, Cynthia
中科院分区：
文献类型：
--
作者：
Galvin, Katherine E.;Ye, Hong;Wetmore, Cynthia
Sonic Hedgehog(Shh)是维持神经干细胞(NSCs)增殖所必需的物质，但其作用机制尚不清楚。而Shh信号的主要介导物Gli1、Gli2和Gli3在海马神经祖细胞中均有表达，而Shh处理NSCs仅诱导Gli1的表达。短发夹状RNA使出生后NSCs中Gli1的急性缺失抑制了NSC的增殖，而Gli1的胚系缺失不影响NSC的增殖，提示Gli1的补偿机制可能存在发育上的差异。为了确定Gli1是否足以促进NSC的增殖，我们过表达了这种有丝分裂原，并惊讶地发现Gli1导致NSC增殖减少，细胞周期G2/M期聚集，并导致细胞凋亡。相反，表达Gli1的谱系受限的神经前体细胞表现出4.5倍的增殖促进。对表达Gli1的神经干细胞的表达分析表明，Gadd45a显著诱导细胞周期蛋白A2和Stag1基因的表达，而细胞周期蛋白A2和Stag1基因参与了细胞的G2-M转换和细胞凋亡。此外，Gadd45a的过表达足以部分概括Gli1诱导的神经干细胞G2/M积聚和细胞死亡。与正常干细胞相比，肿瘤干细胞具有明显更高的基础Gli1表达，并且不会随着Gli1的进一步升高而发生凋亡。我们的数据表明，Gli1诱导的细胞凋亡可能是对过早有丝分裂的一种保护机制，并可能在潜在转化有丝分裂信号的背景下深入了解非恶性干细胞抑制过度增殖的机制。肿瘤干细胞显然缺乏这些机制，这可能是它们不受限制的增殖和恶性潜能的原因之一。
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.