RBPJκ-Dependent Signaling Is Essential for Long-Term Maintenance of Neural Stem Cells in the Adult Hippocampus
RBPJκ-Dependent Signaling Is Essential for Long-Term Maintenance of Neural Stem Cells in the Adult Hippocampus
复制标题
DOI：
10.1523/jneurosci.1567-10.2010
复制
发表时间：
2010-10-13
影响因子：
5.3
通讯作者：
Lie, D. Chichung
中科院分区：
文献类型：
--
作者：
Ehm, Oliver;Goritz, Christian;Lie, D. Chichung
成年海马齿状回神经干细胞产生的新神经元有助于学习和情绪调节。为了终生维持海马神经发生，必须严格控制神经干细胞库的维持。我们发现Notch/RBPJ κ信号通路在成年小鼠海马的神经干细胞中高度活跃。体内神经干细胞中RBPJ κ的条件性失活导致在早期时间点成年海马中神经干细胞的神经元分化增加，并且在稍后的时间点耗尽Sox 2阳性神经干细胞池并抑制海马神经发生。此外，RBPJ κ缺陷型神经干细胞在体外表现出自我更新受损和转录因子Sox 2表达缺失。有趣的是，我们发现Notch信号传导增加了成人神经干细胞中Sox 2启动子活性和Sox 2表达。此外，激活的Notch和RBPJ κ在成年海马神经干细胞中高度富集在Sox 2启动子上，从而鉴定Sox 2为Notch/RBPJ κ信号传导的直接靶标。最后，我们发现过表达Sox 2可以挽救RBPJ κ缺陷神经干细胞的自我更新缺陷。这些结果确定RBPJ κ依赖性途径作为成人神经干细胞维持的重要调节因子，并表明RBPJ κ的作用至少部分是由Sox 2表达的控制介导的。
The generation of new neurons from neural stem cells in the adult hippocampal dentate gyrus contributes to learning and mood regulation. To sustain hippocampal neurogenesis throughout life, maintenance of the neural stem cell pool has to be tightly controlled. We found that the Notch/RBPJ kappa-signaling pathway is highly active in neural stem cells of the adult mouse hippocampus. Conditional inactivation of RBPJ kappa in neural stem cells in vivo resulted in increased neuronal differentiation of neural stem cells in the adult hippocampus at an early time point and depletion of the Sox2-positive neural stem cell pool and suppression of hippocampal neurogenesis at a later time point. Moreover, RBPJ kappa-deficient neural stem cells displayed impaired self-renewal in vitro and loss of expression of the transcription factor Sox2. Interestingly, we found that Notch signaling increases Sox2 promoter activity and Sox2 expression in adult neural stem cells. In addition, activated Notch and RBPJ kappa were highly enriched on the Sox2 promoter in adult hippocampal neural stem cells, thus identifying Sox2 as a direct target of Notch/RBPJ kappa signaling. Finally, we found that overexpression of Sox2 can rescue the self-renewal defect in RBPJ kappa-deficient neural stem cells. These results identify RBPJ kappa-dependent pathways as essential regulators of adult neural stem cell maintenance and suggest that the actions of RBPJ kappa are, at least in part, mediated by control of Sox2 expression.