Notch pathway molecules are essential for the maintenance, but not the generation, of mammalian neural stem cells
Notch pathway molecules are essential for the maintenance, but not the generation, of mammalian neural stem cells
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DOI：
10.1101/gad.975202
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发表时间：
2002-04-01
影响因子：
10.5
通讯作者：
van der Kooy, D
中科院分区：
文献类型：
--
作者：
Hitoshi, S;Alexson, T;van der Kooy, D
具有自我更新和多潜能的神经干细胞产生于早期胚胎脑中，并在整个生命周期中维持。其产生和维持的机制在很大程度上是未知的。在这里，我们表明，神经干细胞的产生独立于RBP-Jkappa，在Notch信号的关键分子，通过使用RBP-Jkappa（-/-）胚胎干细胞在胚胎干细胞衍生的神经球测定。然而，Notch通路分子对于维持神经干细胞是必不可少的;它们在RBP-Jkappa（-/-）或Notch 1（-/-）小鼠的早期胚胎脑中被耗尽。神经干细胞在缺乏早老素1（PS1）基因（Notch信号传导的关键调节因子）的胚胎脑中也会耗尽，并且在PS1（+/-）成人脑中减少。神经元和神经胶质细胞的分化在体外增强衰减的Notch信号和抑制表达的活性形式的Notch 1。这些数据与Notch信号传导在神经干细胞维持中的作用一致，并且与神经元/神经胶质命运开关中的作用不一致。
Neural stem cells, which exhibit self-renewal and multipotentiality, are generated in early embryonic brains and maintained throughout the lifespan. The mechanisms of their generation and maintenance are largely unknown. Here, we show that neural stem cells are generated independent of RBP-Jkappa, a key molecule in Notch signaling, by using RBP-Jkappa(-/-) embryonic stem cells in an embryonic stem cell-derived neurosphere assay. However, Notch pathway molecules are essential for the maintenance of neural stem cells; they are depleted in the early embryonic brains of RBP-Jkappa(-/-) or Notch1(-/-) mice. Neural stem cells also are depleted in embryonic brains deficient for the presenilin1 (PS1) gene, a key regulator in Notch signaling, and are reduced in PS1(+/-) adult brains. Both neuronal and glial differentiation in vitro were enhanced by attenuation of Notch signaling and suppressed by expressing an active form of Notch1. These data are consistent with a role for Notch signaling in the maintenance of the neural stem cell, and inconsistent with a role in a neuronal/glial fate switch.