A MIG-15/JNK-1 MAP kinase cascade opposes RPM-1 signaling in synapse formation and learning.
A MIG-15/JNK-1 MAP kinase cascade opposes RPM-1 signaling in synapse formation and learning.
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DOI：
10.1371/journal.pgen.1007095
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发表时间：
2017-12
期刊：
影响因子：
4.5
通讯作者：
Grill B
中科院分区：
文献类型：
--
作者：
Crawley O;Giles AC;Desbois M;Kashyap S;Birnbaum R;Grill B
Pam/Highwire/RPM-1 （PHR）蛋白是保守的细胞内信号中枢，调节突触形成和轴突终止。秀丽隐杆线虫PHR蛋白，称为RPM-1，作为泛素连接酶抑制DLK-1和MLK-1 MAP激酶途径。在rpm-1突变体的机械感觉神经元中，我们已经确定了几种可能形成新的MAP激酶途径的激酶，该途径抑制突触形成缺陷，但不抑制轴突终止缺陷。该通路包括：MIG-15 （MAP4K）、NSY-1 （MAP3K）、JKK-1 （MAP2K）和JNK-1 （MAPK）。在野生型动物中，转基因过表达MIG-15/JNK-1通路中的激酶足以破坏突触的形成。MIG-15/JNK-1通路在机械感觉神经元中具有细胞自主功能，这些激酶定位于突触前末端，这进一步证明了其在突触发育中的作用。MIG-15/JNK-1信号的缺失也抑制了rpm-1突变体对重复机械刺激的习惯缺陷，这是一种可能由谷氨酸突触形成受损引起的行为缺陷。有趣的是，习惯化结果与MIG-15/JNK-1途径作为与RPM-1平行的相反途径一致。这些发现表明，MIG-15/JNK-1通路可以限制谷氨酸突触的形成和短期学习。我们在线虫C.秀丽隐杆线虫体内探索了控制突触形成的分子机制。我们的研究结果已经确定了保守的MIG-15/JNK-1 MAPK通路，该通路限制机械感觉神经元中谷氨酸能神经元突触的形成，但不限制运动神经元突触的形成。这可能具有重要意义，因为机械感觉神经元形成的突触与哺乳动物中枢神经系统中的突触相似，而对体内影响中枢突触形成的信号所知相对较少。有趣的是，我们的结果与MIG-15/JNK-1途径对抗RPM-1是一致的，RPM-1是一种抑制不同JNK和p38信号通路的信号中枢和泛素连接酶。这表明RPM-1可能抑制特定的MAPK通路，如DLK-1通路，而不是简单地作为神经元中JNK和p38信号的一般抑制剂。考虑到JNK - MAPK信号与神经退行性疾病（如阿尔茨海默病）之间的联系，我们的研究结果特别有趣。
The Pam/Highwire/RPM-1 (PHR) proteins are conserved intracellular signaling hubs that regulate synapse formation and axon termination. The C. elegans PHR protein, called RPM-1, acts as a ubiquitin ligase to inhibit the DLK-1 and MLK-1 MAP kinase pathways. We have identified several kinases that are likely to form a new MAP kinase pathway that suppresses synapse formation defects, but not axon termination defects, in the mechanosensory neurons of rpm-1 mutants. This pathway includes: MIG-15 (MAP4K), NSY-1 (MAP3K), JKK-1 (MAP2K) and JNK-1 (MAPK). Transgenic overexpression of kinases in the MIG-15/JNK-1 pathway is sufficient to impair synapse formation in wild-type animals. The MIG-15/JNK-1 pathway functions cell autonomously in the mechanosensory neurons, and these kinases localize to presynaptic terminals providing further evidence of a role in synapse development. Loss of MIG-15/JNK-1 signaling also suppresses defects in habituation to repeated mechanical stimuli in rpm-1 mutants, a behavioral deficit that is likely to arise from impaired glutamatergic synapse formation. Interestingly, habituation results are consistent with the MIG-15/JNK-1 pathway functioning as a parallel opposing pathway to RPM-1. These findings indicate the MIG-15/JNK-1 pathway can restrict both glutamatergic synapse formation and short-term learning. We explored the molecular mechanisms that govern synapse formation in vivo using the nematode C. elegans. Our results have identified a conserved MIG-15/JNK-1 MAPK pathway that restricts formation of glutamatergic, neuron-neuron synapses in the mechanosensory neurons, but does not restrict synapse formation in motor neurons. This could have important implications because synapses made by the mechanosensory neurons are reminiscent of synapses in the mammalian central nervous system, and relatively little is known about the signals that specifically influence central synapse formation in vivo. Interestingly, our results are consistent with the MIG-15/JNK-1 pathway opposing RPM-1, a signaling hub and ubiquitin ligase that inhibits different JNK and p38 signaling pathways. This suggests RPM-1 might inhibit specific MAPK pathways, such as the DLK-1 pathway, rather than simply acting as a general inhibitor of JNK and p38 signaling in neurons. Our results are particularly interesting given emerging links between JNK MAPK signaling and neurodegenerative diseases, such as Alzheimer’s disease.
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DOI：
10.1534/g3.115.021410
发表时间：
2015-10-13
期刊：
G3 (Bethesda, Md.)
影响因子：
--
作者：
Giles AC;Opperman KJ;Rankin CH;Grill B
通讯作者：
Grill B
影响因子：
3.3
作者：
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DOI：
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发表时间：
2013-09-02
期刊：
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影响因子：
--
作者：
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通讯作者：
Lewcock JW
DOI：
10.1073/pnas.1410263111
发表时间：
2014-11-18
影响因子：
11.1
作者：
Chen, Chun-Hao;Lee, Albert;Pan, Chun-Liang
通讯作者：
Pan, Chun-Liang
影响因子：
4.5
作者：
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通讯作者：
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