Institute for Virus Research, Kyoto University, Sakyo-ku, Kyoto, Japan.
J Neurosci. 2010 Mar 3;30(9):3489-98. doi: 10.1523/JNEUROSCI.4987-09.2010.
Activation of Notch signaling induces the expression of transcriptional repressor genes such as Hes1, leading to repression of proneural gene expression and maintenance of neural stem/progenitor cells. However, a requirement for Notch signaling in the telencephalon was not clear, because in Hes1;Hes3;Hes5 triple-mutant mice, neural stem/progenitor cells are depleted in most regions of the developing CNS, but not in the telencephalon. Here, we investigated a role for Notch signaling in the telencephalon by generating tamoxifen-inducible conditional knock-out mice that lack Rbpj, an intracellular signal mediator of all Notch receptors. When Rbpj was deleted in the embryonic brain, almost all telencephalic neural stem/progenitor cells prematurely differentiated into neurons and were depleted. When Rbpj was deleted in the adult brain, all neural stem cells differentiated into transit-amplifying cells and neurons. As a result, neurogenesis increased transiently, but 3 months later all neural stem cells were depleted and neurogenesis was totally lost. These results indicated an absolute requirement of Notch signaling for the maintenance of neural stem cells and a proper control of neurogenesis in both embryonic and adult brains.
Notch 信号的激活诱导转录抑制因子基因如 Hes1 的表达，导致神经前体细胞基因表达的抑制和神经干细胞/祖细胞的维持。然而，Notch 信号在端脑中的作用尚不清楚，因为在 Hes1;Hes3;Hes5 三重突变小鼠中，神经干细胞/祖细胞在大多数发育中的中枢神经系统区域被耗尽，但在端脑中没有。在这里，我们通过生成缺乏 Rbpj 的他莫昔芬诱导型条件敲除小鼠来研究 Notch 信号在端脑中的作用，Rbpj 是所有 Notch 受体的细胞内信号介质。当 Rbpj 在胚胎大脑中被删除时，几乎所有的端脑神经干细胞/祖细胞都过早地分化为神经元并被耗尽。当 Rbpj 在成年大脑中被删除时，所有的神经干细胞都分化为过渡扩增细胞和神经元。结果，神经发生短暂增加，但 3 个月后，所有的神经干细胞都被耗尽，神经发生完全丧失。这些结果表明 Notch 信号对于维持神经干细胞和适当控制胚胎和成年大脑中的神经发生是绝对必需的。
