Inserm Unité 952, Centre National de la Recherche Scientifique Unité Mixte de Recherche 7224, Paris, France.
J Neurosci. 2010 Jun 9;30(23):7804-16. doi: 10.1523/JNEUROSCI.0372-10.2010.
c-Jun N-terminal kinases (JNKs) (comprising JNK1-3 isoforms) are members of the MAPK (mitogen-activated protein kinase) family, activated in response to various stimuli including growth factors and inflammatory cytokines. Their activation is facilitated by scaffold proteins, notably JNK-interacting protein-1 (JIP1). Originally considered to be mediators of neuronal degeneration in response to stress and injury, recent studies support a role of JNKs in early stages of neurite outgrowth, including adult axonal regeneration. However, the function of individual JNK isoforms, and their potential effector molecules, remained unknown. Here, we analyzed the role of JNK signaling during axonal regeneration from adult mouse dorsal root ganglion (DRG) neurons, combining pharmacological JNK inhibition and mice deficient for each JNK isoform and for JIP1. We demonstrate that neuritogenesis is delayed by lack of JNK2 and JNK3, but not JNK1. JNK signaling is further required for sustained neurite elongation, as pharmacological JNK inhibition resulted in massive neurite retraction. This function relies on JNK1 and JNK2. Neurite regeneration of jip1(-/-) DRG neurons is affected at both initiation and extension stages. Interestingly, activated JNKs (phospho-JNKs), as well as JIP1, are also present in the cytoplasm of sprouting or regenerating axons, suggesting a local action on cytoskeleton proteins. Indeed, we have shown that JNK1 and JNK2 regulate the phosphorylation state of microtubule-associated protein MAP1B, whose role in axonal regeneration was previously characterized. Moreover, lack of MAP1B prevents neurite retraction induced by JNK inhibition. Thus, signaling by individual JNKs is differentially implicated in the reorganization of the cytoskeleton, and neurite regeneration.
c-Jun N-末端激酶（JNKs）（包括 JNK1-3 同工型）是丝裂原激活蛋白激酶（MAPK）家族的成员，其活性受到各种刺激的调节，包括生长因子和炎性细胞因子。它们的激活是由支架蛋白（特别是 JNK 相互作用蛋白-1（JIP1））介导的。最初被认为是神经元在应激和损伤时退化的介质，最近的研究支持 JNK 在轴突生长的早期阶段发挥作用，包括成年轴突再生。然而，单个 JNK 同工型的功能及其潜在的效应分子仍不清楚。在这里，我们结合药理学 JNK 抑制和缺乏每个 JNK 同工型和 JIP1 的小鼠，分析了 JNK 信号在成年小鼠背根神经节（DRG）神经元轴突再生过程中的作用。我们证明缺乏 JNK2 和 JNK3 会延迟神经发生，但缺乏 JNK1 不会。JNK 信号对于持续的轴突伸长也是必需的，因为药理学 JNK 抑制会导致大量轴突回缩。这个功能依赖于 JNK1 和 JNK2。jip1（-/-）DRG 神经元的轴突再生在起始和延伸阶段都受到影响。有趣的是，激活的 JNKs（磷酸化 JNKs）以及 JIP1，也存在于发芽或再生轴突的细胞质中，表明它们对细胞骨架蛋白有局部作用。事实上，我们已经表明 JNK1 和 JNK2 调节微管相关蛋白 MAP1B 的磷酸化状态，MAP1B 在轴突再生中的作用以前已经被描述过。此外，缺乏 MAP1B 可以防止 JNK 抑制诱导的轴突回缩。因此，单个 JNK 的信号传导在细胞骨架的重组和轴突再生中具有不同的作用。
