Neuronal activity-dependent local activation of dendritic unfolded protein response promotes expression of brain-derived neurotrophic factor in cell soma.
Neuronal activity-dependent local activation of dendritic unfolded protein response promotes expression of brain-derived neurotrophic factor in cell soma.
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DOI：
10.1111/jnc.14221
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发表时间：
2018-01
影响因子：
4.7
通讯作者：
Imaizumi K
中科院分区：
文献类型：
--
作者：
Saito A;Cai L;Matsuhisa K;Ohtake Y;Kaneko M;Kanemoto S;Asada R;Imaizumi K
未折叠蛋白反应（Unfolded protein response，UPR）不仅可以解决内质网应激引起的未折叠蛋白的积累，还可以调节细胞的生理功能。已知提供UPR信号传导分支的ER应激转换器定位于神经元的远端树突状ER。这些报告表明，局部激活的UPR分支可能会产生集成输出的远程通信，并允许在高度极化的神经元的本地事件的调节。在这里，我们证明了UPR信号传导的突触活性和脑源性神经营养因子（BDNF）依赖性局部激活可能与树突功能通过逆行信号传播相关，通过使用鼠神经母细胞瘤细胞系Neuro-2A和来自出生后第0天窝C57 BL/6小鼠的原代培养海马神经元。ER应激传感器，肌醇需要激酶1（IRE 1），在突触后被激活，以响应兴奋性突触激活。激活的树突状IRE 1加速了下游转录因子x盒结合蛋白1（XBP 1）在细胞核中的积累。有趣的是，兴奋性突触激活依赖性的XBP 1上调直接促进了BDNF的转录激活。BDNF反过来以蛋白激酶A依赖的方式通过IRE 1-XBP 1途径驱动其自身的表达。BDNF的外源性处理通过蛋白激酶A-IRE 1-XBP 1级联促进树突的延伸和分支。总之，我们的研究结果表明，索马和极化神经元的远端位点之间的通信是由IRE 1-XBP 1信号的局部激活协调的新机制。树突状IRE 1-XBP 1级联的突触活性和BDNF依赖性不同激活驱动细胞索马中的BDNF表达，并可能参与树突状延伸。 本期封面图片：doi。10.1111/jnc.14159。
Unfolded protein response (UPR) has roles not only in resolving the accumulation of unfolded proteins owing to endoplasmic reticulum (ER) stress, but also in regulation of cellular physiological functions. ER stress transducers providing the branches of UPR signaling are known to localize in distal dendritic ER of neurons. These reports suggest that local activation of UPR branches may produce integrated outputs for distant communication, and allow regulation of local events in highly polarized neurons. Here, we demonstrated that synaptic activity‐ and brain‐derived neurotrophic factor (BDNF)‐dependent local activation of UPR signaling could be associated with dendritic functions through retrograde signal propagation by using murine neuroblastoma cell line, Neuro‐2A and primary cultured hippocampal neurons derived from postnatal day 0 litter C57BL/6 mice. ER stress transducer, inositol‐requiring kinase 1 (IRE1), was activated at postsynapses in response to excitatory synaptic activation. Activated dendritic IRE1 accelerated accumulation of the downstream transcription factor, x‐box‐binding protein 1 (XBP1), in the nucleus. Interestingly, excitatory synaptic activation‐dependent up‐regulation of XBP1 directly facilitated transcriptional activation of BDNF. BDNF in turn drove its own expression via IRE1‐XBP1 pathway in a protein kinase A‐dependent manner. Exogenous treatment with BDNF promoted extension and branching of dendrites through the protein kinase A‐IRE1‐XBP1 cascade. Taken together, our findings indicate novel mechanisms for communication between soma and distal sites of polarized neurons that are coordinated by local activation of IRE1‐XBP1 signaling. Synaptic activity‐ and BDNF‐dependent distinct activation of dendritic IRE1‐XBP1 cascade drives BDNF expression in cell soma and may be involved in dendritic extension. Cover Image for this issue: doi. 10.1111/jnc.14159.
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