The GSK3-MAP1B pathway controls neurite branching and microtubule dynamics
The GSK3-MAP1B pathway controls neurite branching and microtubule dynamics
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DOI：
10.1016/j.mcn.2016.01.001
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发表时间：
2016-04-01
影响因子：
3.5
通讯作者：
Nothias, Fatiha
中科院分区：
文献类型：
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作者：
Barnat, Monia;Benassy, Marie-Noelle;Nothias, Fatiha
微管相关蛋白MAP 1B在轴突再生中起关键作用。我们研究了GSK 3介导的MAP 1B磷酸化在神经突分支局部微调和微管（MT）动力学中的作用。在野生型成人背根神经节（DRG）神经元中，MAP 1B磷酸化在分支点局部减少，生长锥和远端神经突轴的分支动力学在GSK 3抑制后增加。虽然map 1b-/-神经突起，显示增加的分支，不受GSK 3抑制，转染map 1b-/-神经元全长map 1b-cDNA恢复野生型分支表型，表明MAP 1B是一个关键的效应GSK 3下游。在缺乏酪氨酸化MT的突变小鼠中的实验表明磷酸-MAP 1B与酪氨酸化MT的优先关联。有趣的是，在map 1b-cDNA转染的成纤维细胞中，抑制GSK 3介导的MAP 1B磷酸化可以保护酪氨酸化和乙酰化的MT免受诺考达唑诱导的解聚，而在MAP 1B存在下，去酪氨酸化的MT不那么丰富。因此，我们的数据提供了新的见解GSK 3，MAP 1B，神经突分支和MT稳定性调节之间的分子联系。我们认为，在分支点，MAP 1B经历了精细的调节其磷酸化和亚细胞量，以调节乙酰化，脱酪氨酸，和酪氨酸微管池之间的局部平衡。(C)2016 Elsevier Inc. All rights reserved.
The microtubule-associated protein MAP1B plays a key role in axon regeneration. We investigated the role of GSK3-mediated MAP1B phosphorylation in local fine-tuning of neurite branching and the underlying microtubule (MT) dynamics.In wildtype adult dorsal root ganglia (DRG) neurons, MAP1B phosphorylation is locally reduced at branching points, and branching dynamics from growth cones and distal neurite shafts is increased upon GSK3 inhibition. While map1b-/- neurites, that display increased branching, are not affected by GSK3 inhibition, transfection of map1b-/- neurons with full-length map1b-cDNA restores the wildtype branching phenotype, demonstrating that MAP1B is a key effector downstream of GSK3. Experiments in mutant mice lacking tyrosinated MTs indicate a preferential association of phospho-MAP1B with tyrosinated MTs. Interestingly, inhibition of GSK3-mediated MAP1B phosphorylation in map1b-cDNA-transfected fibroblasts protects both tyrosinated and acetylated MTs from nocodazole-induced depolymerization, while detyrosinated MTs are less abundant in the presence of MAP1B. Our data thus provide new insight into the molecular link between GSK3, MAP1B, neurite branching and MT stability regulation. We suggest that, at branching points, MAP1B undergoes a fine regulation of both its phosphorylation and sub-cellular amounts, in order to modulate the local balance between acetylated, detyrosinated, and tyrosinated microtubule pools. (C) 2016 Elsevier Inc. All rights reserved.