美国加州大学旧金山分校的Brenda L. Bloodgood小组取得一项新进展。他们的研究表明刺激特异的NPAS4异二聚体对神经元去极化进行基因组解码。相关论文于2019年10月3日发表于国际学术期刊《细胞》。

研究人员表示，细胞响应明显的外部刺激来调节基因表达。在神经元中，去极化引起诱导型转录因子（ITF）的表达，从而指导后续基因调控。去极化通过兴奋性突触后电位（EPSP）编码神经元的动作电位（AP）输出和突触输入。但是，尚不清楚ITF是否可以将不同类型的电活动转换为基因组调控的不同模式。

研究人员发现，小鼠海马神经元中的AP和EPSP触发了两个空间分隔和分子上不同的诱导机制，导致ITF NPAS4的表达。这两种途径最终形成了具有刺激性的NPAS4异二聚体，这些异二聚体表现出独特的DNA结合模式。因此，NPAS4通过差异传递神经元的刺激输出和突触输入到细胞核，从而使基因调节适应于沿着神经元体树突轴的去极化活性类型。

附：英文原文

Title: Genomic Decoding of Neuronal Depolarization by Stimulus-Specific NPAS4 Heterodimers

Author: G. Stefano Brigidi, Michael G.B. Hayes, Nathaniel P. Delos Santos, Andrea L. Hartzell, Lorane Texari, Pei-Ann Lin, Anna Bartlett, Joseph R. Ecker, Christopher Benner, Sven Heinz, Brenda L. Bloodgood

Issue&Volume: 2019/10/03

Abstract: 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 neurons 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 neurons 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.

DOI: 10.1016/j.cell.2019.09.004

Source: https://www.cell.com/cell/fulltext/S0092-8674(19)31010-4