Benowitz L I, Goldberg D E, Irwin N
Laboratories for Neuroscience Research in Neurosurgery, Children's Hospital, Boston MA 02115, USA.
Restor Neurol Neurosci. 2001;19(1-2):41-9.
Axon growth is characterized by a distinctive program of gene expression. We present evidence here that this program is regulated through a purine-sensitive mechanism, and that it can be re-activated in mature CNS neurons to induce extensive axon growth in vitro and in vivo. In dissociated goldfish retinal ganglion cells, the purine nucleoside inosine acts intracellularly to stimulate axon outgrowth by inducing the expression of GAP-43, Talpha-1 tubulin, and other growth-associated proteins. The purine analog 6-thioguanine (6-TG) acts in the opposite fashion, blocking axon growth and the underlying program of molecular changes. Prior studies in PC12 cells have shown that 6-TG selectively inhibits the activity of N-kinase, a 47-49 kDa serine-threonine kinase. Inosine acts as a competitor of 6-TG, suggesting that it acts as an N-kinase agonist, and that this kinase is part of a modular signal transduction pathway controlling axon growth. Following unilateral transections of the corticospinal tract in mature rats, inosine applied to the intact sensorimotor cortex stimulated layer 5 pyramidal cells to upregulate GAP-43 expression and to sprout axon collaterals that crossed the midline and reinnervated regions of the cervical spinal cord which had lost their normal afferents. It will now be important to identify the molecular changes that lie upstream and downstream of N-kinase, and to explore the clinical potential of activating this pathway in patients who have sustained CNS injury.
轴突生长具有独特的基因表达程序。我们在此提供证据表明，该程序通过嘌呤敏感机制进行调节，并且在成熟的中枢神经系统神经元中可以重新激活，以在体外和体内诱导广泛的轴突生长。在解离的金鱼视网膜神经节细胞中，嘌呤核苷肌苷在细胞内起作用，通过诱导GAP - 43、Tα-1微管蛋白和其他生长相关蛋白的表达来刺激轴突生长。嘌呤类似物6-硫鸟嘌呤（6-TG）则以相反的方式起作用，阻断轴突生长和潜在的分子变化程序。先前在PC12细胞中的研究表明，6-TG选择性抑制N-激酶的活性，N-激酶是一种47-49 kDa的丝氨酸-苏氨酸激酶。肌苷作为6-TG的竞争者，表明它作为N-激酶激动剂起作用，并且该激酶是控制轴突生长的模块化信号转导途径的一部分。在成熟大鼠的皮质脊髓束单侧横断后，将肌苷应用于完整的感觉运动皮层，刺激第5层锥体细胞上调GAP-43表达，并长出轴突侧支，这些侧支穿过中线并重新支配已失去正常传入神经的颈脊髓区域。现在，确定N-激酶上游和下游的分子变化，并探索在遭受中枢神经系统损伤的患者中激活该途径的临床潜力将很重要。
