Department of Molecular Cellular and Developmental Biology, University of Michigan, Ann Arbor, Michigan 48109-1048, USA.
J Neurosci. 2013 Jul 31;33(31):12764-78. doi: 10.1523/JNEUROSCI.5160-12.2013.
Mitogen-activated protein (MAP) kinase signaling cascades orchestrate diverse cellular activities with common molecular players. To achieve specific cellular outcomes in response to specific signals, scaffolding proteins play an important role. Here we investigate the role of the scaffolding protein JNK interacting protein-1 (JIP1) in neuronal signaling by a conserved axonal MAP kinase kinase kinase, known as Wallenda (Wnd) in Drosophila and dual leucine kinase (DLK) in vertebrates and Caenorhabditis elegans. Recent studies in multiple model organisms suggest that Wnd/DLK regulates both regenerative and degenerative responses to axonal injury. Here we report a new role for Wnd in regulating synaptic structure during development, which implies that Wnd is also active in uninjured neurons. This synaptic role of Wnd can be functionally separated from the role of Wnd in axonal regeneration and injury signaling by the requirement for the JIP1 scaffold and the p38b MAP kinase. JIP1 mediates the synaptic function of Wnd via p38, which is not required for injury signaling or new axonal growth after injury. Our results indicate that Wnd regulates multiple independent pathways in Drosophila motoneurons and that JIP1 scaffolds a specific downstream cascade required for the organization of presynaptic microtubules during synaptic development.
丝裂原活化蛋白（MAP）激酶信号级联通过共同的分子成分协调各种细胞活动。为了针对特定信号实现特定的细胞结果，支架蛋白发挥着重要作用。在这里，我们通过一种保守的轴突 MAP 激酶激酶激酶（在果蝇中称为 Wallenda（Wnd），在脊椎动物和秀丽隐杆线虫中称为双重亮氨酸激酶（DLK））研究了支架蛋白 JNK 相互作用蛋白 1（JIP1）在神经元信号传导中的作用。在多种模式生物中的最新研究表明，Wnd/DLK 调节轴突损伤后的再生和退化反应。在这里，我们报告了 Wnd 在发育过程中调节突触结构的新作用，这意味着 Wnd 在未受伤的神经元中也具有活性。Wnd 在轴突再生和损伤信号传导中的作用可以通过 JIP1 支架和 p38b MAP 激酶的要求从 Wnd 在调节突触结构中的作用中分离出来。JIP1 通过 p38 介导 Wnd 的突触功能，这对于损伤信号传导或损伤后新轴突生长不是必需的。我们的结果表明，Wnd 在果蝇运动神经元中调节多个独立的途径，并且 JIP1 支架是在突触发育过程中调节突触前微管组织所必需的特定下游级联。
