Salinas P C
Developmental Biology Research Centre, Randall Institute, King's College London, U.K.
Biochem Soc Symp. 1999;65:101-9.
Wiring' of the central nervous system is accomplished by the precise and co-ordinated behaviour of neuronal cells. Proper navigation of axons and formation of synaptic contacts with the correct targets are essential. Although several signalling molecules that control axon guidance, target selection and formation of synapses have been identified, little is known about how these proteins lead to changes in the axonal cytoskeleton. Wnt signalling factors have been shown to induce axonal remodelling in developing neurons. As several components of the Wnt signalling pathway are known, studies on Wnt factors could elucidate the mechanisms by which extracellular molecules regulate the neuronal cytoskeleton. Wnt-7a induces axonal spreading and subsequent increases in synaptic protein levels in mouse cerebellar neurons. These findings suggest a role for Wnt-7a in axon guidance and synapse formation in the developing cerebellum. Based on analyses of the axonal cytoskeleton, a model is proposed in which Wnt-7a induces axonal remodelling by inhibiting glycogen synthase kinase-3 beta (GSK-3 beta), a serine/threonine kinase. Inhibition of GSK-3 beta leads to a decrease in a phosphorylated form of microtubule-associated protein-1B (MAP-1B), a protein involved in microtubule assembly, and a concomitant decrease in the level of stable microtubules. This chapter discusses the novel role of Wnt factors in regulating the axonal cytoskeleton during neuronal development.
中枢神经系统的“布线”是由神经元细胞精确且协调的行为完成的。轴突的正确导向以及与正确靶标形成突触连接至关重要。尽管已经鉴定出了几种控制轴突导向、靶标选择和突触形成的信号分子，但对于这些蛋白质如何导致轴突细胞骨架发生变化却知之甚少。Wnt信号因子已被证明可诱导发育中的神经元发生轴突重塑。由于已知Wnt信号通路的几个组成部分，对Wnt因子的研究可能会阐明细胞外分子调节神经元细胞骨架的机制。Wnt-7a可诱导小鼠小脑神经元的轴突伸展并随后增加突触蛋白水平。这些发现表明Wnt-7a在发育中的小脑中的轴突导向和突触形成中发挥作用。基于对轴突细胞骨架的分析，提出了一个模型，其中Wnt-7a通过抑制丝氨酸/苏氨酸激酶糖原合酶激酶-3β（GSK-3β）来诱导轴突重塑。抑制GSK-3β会导致参与微管组装的微管相关蛋白-1B（MAP-1B）的磷酸化形式减少，同时稳定微管水平也随之降低。本章讨论了Wnt因子在神经元发育过程中调节轴突细胞骨架的新作用。
