Neurogenic Subventricular Zone Stem/Progenitor Cells Are Notch1-Dependent in Their Active But Not Quiescent State
Neurogenic Subventricular Zone Stem/Progenitor Cells Are Notch1-Dependent in Their Active But Not Quiescent State
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DOI：
10.1523/jneurosci.0455-12.2012
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发表时间：
2012-04-18
影响因子：
5.3
通讯作者：
Taylor, Verdon
中科院分区：
文献类型：
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作者：
Basak, Onur;Giachino, Claudio;Taylor, Verdon
成年哺乳动物的前脑含有神经干/祖细胞(NSCs)，这些细胞在一生中都能产生神经元。就像在其他体细胞干细胞系统中一样，神经干细胞被认为主要是静止的，只有零星地增殖才能产生更可靠的后代。然而，最近的研究表明，静止并不是干细胞的基本标准。目前尚不清楚神经干细胞是否因其增殖状态而表现出不同的分子依赖性。成年小鼠脑的脑室下区(SVZ)具有显著的神经干细胞激活修复能力。成年神经干细胞在神经发生或再生过程中的分子相互作用尚不清楚，但解决这些相互作用对于了解脑内稳态和修复至关重要。利用条件遗传学和命运图谱，我们证明了Notch信号在SVZ的神经发生中是必不可少的。通过镶嵌分析，我们发现了活跃的神经源性和再生性神经干细胞在Notch依赖性方面的惊人差异。虽然激活和再生的神经干细胞都依赖于规范的Notch信号，但Notch1缺失会导致选择性地丢失激活的神经干细胞(ANSC)。与之形成鲜明对比的是，静止的神经干细胞(QNSCs)在Notch1消融后一直存在，直到在再生或衰老过程中被诱导，于是它们变得依赖Notch1，无法完全恢复神经发生。我们的结果表明，Notch1是成体SVZ生态位的关键组成部分，促进了aNSCs的维持，这一功能在qNSCs中得到了补偿。因此，我们证实了Notch信号在维持成年SVZ神经干细胞和神经发生中的重要性，并揭示了NSCs对Notch1的选择性依赖，这可能是由有丝分裂状态决定的。
The adult mammalian forebrain contains neural stem/progenitor cells (NSCs) that generate neurons throughout life. As in other somatic stem cell systems, NSCs are proposed to be predominantly quiescent and proliferate only sporadically to produce more committed progeny. However, quiescence has recently been shown not to be an essential criterion for stem cells. It is not known whether NSCs show differences in molecular dependence based on their proliferation state. The subventricular zone (SVZ) of the adult mouse brain has a remarkable capacity for repair by activation of NSCs. The molecular interplay controlling adult NSCs during neurogenesis or regeneration is not clear but resolving these interactions is critical in order to understand brain homeostasis and repair. Using conditional genetics and fate mapping, we show that Notch signaling is essential for neurogenesis in the SVZ. By mosaic analysis, we uncovered a surprising difference in Notch dependence between active neurogenic and regenerative NSCs. While both active and regenerative NSCs depend upon canonical Notch signaling, Notch1-deletion results in a selective loss of active NSCs (aNSCs). In sharp contrast, quiescent NSCs (qNSCs) remain after Notch1 ablation until induced during regeneration or aging, whereupon they become Notch1-dependent and fail to fully reinstate neurogenesis. Our results suggest that Notch1 is a key component of the adult SVZ niche, promoting maintenance of aNSCs, and that this function is compensated in qNSCs. Therefore, we confirm the importance of Notch signaling for maintaining NSCs and neurogenesis in the adult SVZ and reveal that NSCs display a selective reliance on Notch1 that may be dictated by mitotic state.