Neural Development Group, Division of Cell & Developmental Biology, College of Life Sciences, University of Dundee, Dow Street, Dundee, DD1 5EH, Scotland, UK.
Dev Biol. 2010 Feb 15;338(2):215-25. doi: 10.1016/j.ydbio.2009.12.001. Epub 2009 Dec 11.
Regulated neuron production within the vertebrate nervous system relies on input from multiple signalling pathways. Work in the Drosophila retina has demonstrated that PI3-kinase and downstream TOR signalling regulate the timing of photoreceptor differentiation; however, the function of such signals during vertebrate neurogenesis is not well understood. Here we show that mutant mice lacking PKB activity downstream of PDK1, the master kinase of the PI3-kinase pathway, exhibit deficient neuron production. We further demonstrate expression of PI3-kinase signalling components and active PKB and TOR signalling in the chick spinal cord, an early site of neurogenesis. Neuron production was also attenuated in the chick neural tube following exposure to small molecule inhibitors of PI3-kinase (LY294002) or TOR (Rapamycin) activity. Furthermore, Rapamycin repressed expression of early neuronal differentiation genes, such as Ngn2, but did not inhibit expression of Sox1B genes characteristic of proliferating neural progenitors. In addition, some cells expressing an early neuronal marker were mis-localised at the ventricular surface in the presence of Rapamycin and remained aberrantly within the cell cycle. These findings suggest that TOR signalling is necessary to initiate neuronal differentiation and that it may facilitate coordination of cell cycle and differentiation programmes. In contrast, stimulating PI3-kinase signalling did not increase neuron production, suggesting that such activity is simply permissive for vertebrate neurogenesis.
脊椎动物神经系统中受调控的神经元产生依赖于来自多个信号通路的输入。果蝇视网膜的研究表明，PI3-激酶和下游 TOR 信号调节光感受器分化的时间；然而，这种信号在脊椎动物神经发生中的功能还不是很清楚。在这里，我们展示了缺乏 PDK1 下游 PKB 活性的突变小鼠表现出神经元产生缺陷。我们还进一步证明了 PI3-激酶信号通路的主激酶 PDK1 下游的 PKB 和 TOR 信号在鸡脊髓中的表达，鸡脊髓是神经发生的早期部位。在鸡神经管中，小分子抑制剂（LY294002，PI3-激酶抑制剂；Rapamycin，TOR 抑制剂）处理后，神经元的产生也减弱了。此外，Rapamycin 抑制了早期神经元分化基因的表达，如 Ngn2，但不抑制增殖神经祖细胞特征的 Sox1B 基因的表达。此外，在 Rapamycin 存在的情况下，一些表达早期神经元标记的细胞在室腔表面发生错位，并在细胞周期中保持异常。这些发现表明 TOR 信号对于启动神经元分化是必要的，并且它可能有助于协调细胞周期和分化程序。相比之下，刺激 PI3-激酶信号不会增加神经元的产生，这表明这种活性对于脊椎动物神经发生仅仅是许可的。
