Neurotrophin-mediated dendrite-to-nucleus signaling revealed by microfluidic compartmentalization of dendrites
Neurotrophin-mediated dendrite-to-nucleus signaling revealed by microfluidic compartmentalization of dendrites
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DOI：
10.1073/pnas.1012401108
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发表时间：
2011-07-05
影响因子：
11.1
通讯作者：
Jaffrey, Samie R.
中科院分区：
文献类型：
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作者：
Cohen, Michael S.;Orth, Carlos Bas;Jaffrey, Samie R.
从树突突触到细胞核的信号传导调节神经元功能的重要方面，包括突触可塑性。神经营养蛋白脑源性神经营养因子（BDNF）可以诱导体内突触的持久强化，这种作用依赖于转录。然而，向细胞核发出信号的机制尚不清楚。在这里，我们描述了一种微流体培养装置，用于研究树突到细胞核的信号传导。使用这些微流体装置，我们证明 BDNF 可以直接作用于树突，引发顺行信号，诱导立即早期基因 Arc 和 c-Fos 的转录。 Arc 的诱导依赖于树突和细胞体来源的钙，而 c-Fos 的诱导不依赖于钙。与依赖 MEK5 的逆行神经营养蛋白介导的轴突到细胞核信号传导相反，BDNF 介导的顺行树突到细胞核信号传导依赖于 MEK1/2。有趣的是，细胞体内需要 TrkB（BDNF 受体）的活性来诱导树突状应用的 BDNF 介导的 Arc 和 c-Fos。这些结果与信号内体样通路的参与一致，该通路将 BDNF 信号从树突传递到细胞核。
Signaling from dendritic synapses to the nucleus regulates important aspects of neuronal function, including synaptic plasticity. The neurotrophin brain-derived neurotrophic factor (BDNF) can induce long-lasting strengthening of synapses in vivo and this effect is dependent on transcription. However, the mechanism of signaling to the nucleus is not well understood. Here we describe a microfluidic culture device to investigate dendrite-to-nucleus signaling. Using these microfluidic devices, we demonstrate that BDNF can act directly on dendrites to elicit an anterograde signal that induces transcription of the immediate early genes, Arc and c-Fos. Induction of Arc is dependent on dendrite- and cell body-derived calcium, whereas induction of c-Fos is calcium-independent. In contrast to retrograde neurotrophin-mediated axon-to-nucleus signaling, which is MEK5-dependent, BDNF-mediated anterograde dendrite-to-nucleus signaling is dependent on MEK1/2. Intriguingly, the activity of TrkB, the BDNF receptor, is required in the cell body for the induction of Arc and c-Fos mediated by dendritically applied BDNF. These results are consistent with the involvement of a signaling endosome-like pathway that conveys BDNF signals from the dendrite to the nucleus.