Genomic Decoding of Neuronal Depolarization by Stimulus-Specific NPAS4 Heterodimers
Genomic Decoding of Neuronal Depolarization by Stimulus-Specific NPAS4 Heterodimers
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DOI：
10.1016/j.cell.2019.09.004
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发表时间：
2019-10-03
期刊：
影响因子：
64.5
通讯作者：
Bloodgood, Brenda L.
中科院分区：
文献类型：
--
作者：
Brigidi, G. Stefano;Hayes, Michael G. B.;Bloodgood, Brenda L.
细胞调节基因表达以响应显著的外部刺激。在神经元中，去极化导致诱导转录因子（ITFs）的表达，从而指导随后的基因调控。去极化通过兴奋性突触后电位（EPSPs）编码神经元的动作电位（AP）输出和突触输入。然而，目前尚不清楚是否不同类型的电活动可以通过ITF转化为不同的基因组调节模式。本研究表明，小鼠海马神经元中的ap和EPSPs触发两种空间分离和分子不同的诱导机制，导致ITF NPAS4的表达。这两种途径最终形成刺激特异性NPAS4异源二聚体，表现出不同的DNA结合模式。因此，NPAS4在神经元的尖峰输出和对细胞核的突触输入中进行了不同的交流，使基因调控能够根据神经元的躯体-树突轴上的去极化活动类型进行调整。
Cells regulate gene expression in response to salient external stimuli. In neurons, depolarization leads to the expression of inducible transcription factors (ITFs) that direct subsequent gene regulation. Depolarization encodes both a neuron's action potential (AP) output and synaptic inputs, via excitatory postsynaptic potentials (EPSPs). However, it is unclear if distinct types of electrical activity can be transformed by an ITF into distinct modes of genomic regulation. Here, we show that APs and EPSPs in mouse hippocampal neurons trigger two spatially segregated and molecularly distinct induction mechanisms that lead to the expression of the ITF NPAS4. These two pathways culminate in the formation of stimulus-specific NPAS4 heterodimers that exhibit distinct DNA binding patterns. Thus, NPAS4 differentially communicates increases in a neuron's spiking output and synaptic inputs to the nucleus, enabling gene regulation to be tailored to the type of depolarizing activity along the somato-dendritic axis of a neuron.