Division of Biological Sciences, Section of Neurobiology, and Howard Hughes Medical Institute, University of California San Diego, La Jolla, California 92093.
J Neurosci. 2014 Jan 15;34(3):758-63. doi: 10.1523/JNEUROSCI.2886-13.2014.
The ability of axons to regrow after injury is determined by the complex interplay of intrinsic growth programs and external cues. In Caenorhabditis elegans mechanosensory neuron, axons exhibit robust regenerative regrowth following laser axotomy. By surveying conserved metabolic signaling pathways, we have identified the ribosomal S6 kinase RSKS-1 as a new cell-autonomous inhibitor of axon regeneration. RSKS-1 is not required for axonal development but inhibits axon regrowth after injury in multiple neuron types. Loss of function in rsks-1 results in more rapid growth cone formation after injury and accelerates subsequent axon extension. The enhanced regrowth of rsks-1 mutants is partly dependent on the DLK-1 MAPK cascade. An essential output of RSKS-1 in axon regrowth is the metabolic sensor AMP kinase, AAK-2. We further show that the antidiabetic drug phenformin, which activates AMP kinase, can promote axon regrowth. Our data reveal a new function for an S6 kinase acting through an AMP kinase in regenerative growth of injured axons.
轴突在受伤后能否再生,取决于内在生长程序和外部线索的复杂相互作用。在秀丽隐杆线虫的机械感觉神经元中,轴突在激光切断后表现出强大的再生性生长。通过调查保守的代谢信号通路,我们已经确定核糖体 S6 激酶 RSKS-1 是轴突再生的新的细胞自主抑制剂。RSKS-1 不是轴突发育所必需的,但在多种神经元类型中抑制损伤后的轴突再生。rsks-1 的功能丧失会导致损伤后生长锥更快形成,并加速随后的轴突延伸。rsks-1 突变体的增强再生部分依赖于 DLK-1 MAPK 级联。RSKS-1 在轴突再生中的一个重要输出是代谢传感器 AMP 激酶 AAK-2。我们进一步表明,一种激活 AMP 激酶的抗糖尿病药物二甲双胍可以促进轴突再生。我们的数据揭示了 S6 激酶通过 AMP 激酶在损伤轴突的再生性生长中的新功能。