Activity-dependent transcription regulation of PSD-95 by neuregulin-1 and Eos
Activity-dependent transcription regulation of PSD-95 by neuregulin-1 and Eos
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DOI：
10.1038/nn1342
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发表时间：
2004-11-01
影响因子：
25
通讯作者：
Ambron, RT
中科院分区：
文献类型：
--
作者：
Bao, JX;Lin, H;Ambron, RT
神经调节蛋白-1 （Nrg-1）含有一个胞内结构域（Nrg-ICD），可易位到细胞核中，在细胞核中调节神经元去极化时的基因表达。然而，其目标启动子的身份及其调节转录的机制一直是难以捉摸的。在小鼠耳蜗中，突触活动增加核Nrg-ICD水平并上调突触后密度蛋白-95 (PSD-95)， PSD-95是一种在突触后结构中富集的支架蛋白。Nrg-ICD通过结合锌指转录因子Eos来增强PSD-95启动子的转录活性。Nrg-ICD-Eos复合物通过一种不依赖于γ分泌酶调节的信号通路诱导体内内源性PSD-95的表达。Nrg-ICD- Eos复合物对PSD-95表达的上调为活动依赖性突触可塑性提供了分子基础。
Neuregulin-1 (Nrg-1) contains an intracellular domain (Nrg-ICD) that translocates into the nucleus, where it may regulate gene expression upon neuronal depolarization. However, the identity of its target promoters and the mechanisms by which it regulates transcription have been elusive. Here we report that, in the mouse cochlea, synaptic activity increases the level of nuclear Nrg-ICD and upregulates postsynaptic density protein-95 (PSD-95), a scaffolding protein that is enriched in post-synaptic structures. Nrg-ICD enhances the transcriptional activity of the PSD-95 promoter by binding to a zinc-finger transcription factor, Eos. The Nrg-ICD-Eos complex induces endogenous PSD-95 expression in vivo through a signaling pathway that is mostly independent of gamma-secretase regulation. This upregulation of PSD-95 expression by the Nrg-ICD- Eos complex provides a molecular basis for activity-dependent synaptic plasticity.