Dawson H N, Ferreira A, Eyster M V, Ghoshal N, Binder L I, Vitek M P
Division of Neurology, Department of Medicine, Duke University, Durham, NC 27710 and OSV, Inc., Research Triangle Park, NC 27709, USA.
J Cell Sci. 2001 Mar;114(Pt 6):1179-87. doi: 10.1242/jcs.114.6.1179.
Conflicting evidence supports a role for tau as an essential neuronal cytoskeletal protein or as a redundant protein whose function can be fulfilled by other microtubule-associated proteins. To investigate the function of tau in axonogenesis, we created tau deficient mice by disrupting the TAU gene. The engineered mice do not express the tau protein, appear physically normal and are able to reproduce. In contrast to a previously reported tau knockout mouse, embryonic hippocampal cultures from tau deficient mice show a significant delay in maturation as measured by axonal and neuritic extensions. The classic technique of selectively enhancing axonal growth by growth on laminin substrates failed to restore normal neuronal maturation of tau knockout neurons. By mating human TAU-gene transgenic and tau knockout mice, we reconstituted tau-deficient neurons with human tau proteins and restored a normal pattern of axonal growth and neuronal maturation. The ability of human tau proteins to rescue tau-deficient mouse neurons confirms that tau expression affects the rate of neurite extension.
相互矛盾的证据支持tau作为一种重要的神经元细胞骨架蛋白，或作为一种冗余蛋白，其功能可由其他微管相关蛋白来实现。为了研究tau在轴突发生中的功能，我们通过破坏TAU基因创建了tau缺陷小鼠。这些基因工程小鼠不表达tau蛋白，外观正常且能够繁殖。与之前报道的tau基因敲除小鼠不同，tau缺陷小鼠的胚胎海马培养物在轴突和神经突延伸方面显示出成熟的显著延迟。通过在层粘连蛋白底物上生长来选择性增强轴突生长的经典技术未能恢复tau基因敲除神经元的正常神经元成熟。通过将人类TAU基因转基因小鼠与tau基因敲除小鼠交配，我们用人tau蛋白重建了tau缺陷神经元，并恢复了轴突生长和神经元成熟的正常模式。人tau蛋白拯救tau缺陷小鼠神经元的能力证实了tau表达会影响神经突延伸的速率。
