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在体条件下对小鼠海马内 MAPK/ERK 依赖性和非依赖性活性调控的转录程序进行分析。

Profiling the MAPK/ERK dependent and independent activity regulated transcriptional programs in the murine hippocampus in vivo.

机构信息

Institute for Theoretical Biology and Institute of Pathology, Charité - Universitätsmedizin Berlin, 10117, Berlin, Germany.

Institute for Molecular and Cellular Cognition, Center for Molecular Neurobiology Hamburg, University Medical Center Hamburg-Eppendorf, 20251, Hamburg, Germany.

出版信息

Sci Rep. 2017 Mar 28;7:45101. doi: 10.1038/srep45101.

Abstract

Activity-dependent alteration of the transcriptional program is central for shaping neuronal connectivity. Constitutively expressed transcription factors orchestrate the initial response to neuronal stimulation and serve as substrates for second messenger-regulated kinase signalling cascades. The mitogen-activated protein kinase ERK conveys signalling from the synapse to the nucleus but its genetic signature following neuronal activity has not been revealed. The goal of the present study was to identify ERK dependent and independent activity regulated transcriptional programs in the murine hippocampus. We used generalized seizures combined with the pharmacological intervention of MEK activation as an in vivo model to determine the complete transcriptional program initiated by ERK after neuronal activity. Our survey demonstrates that the induction of a large number of activity-regulated genes, including Arc/Arg3.1, Arl5b, Gadd45b, Homer1, Inhba and Zwint, is indeed dependent on ERK phosphorylation. In contrast, expression of a small group of genes, including Npas4, Arl4d, Errfi1, and Rgs2, is only partially dependent or completely independent (Ppp1r15a) of this signalling pathway. Among the identified transcripts are long non-coding (lnc) RNAs and induction of LincPint and splice variants of NEAT1 are ERK dependent. Our survey provides a comprehensive analysis of the transcriptomic response conveyed by ERK signalling in the hippocampus.

摘要

活动依赖性的转录程序改变是塑造神经元连接的核心。组成型表达的转录因子协调对神经元刺激的初始反应,并作为第二信使调节激酶信号级联反应的底物。丝裂原活化蛋白激酶 ERK 将信号从突触传递到细胞核,但神经元活动后其遗传特征尚未被揭示。本研究的目的是鉴定在小鼠海马体中 ERK 依赖性和非依赖性活动调节的转录程序。我们使用广义癫痫发作结合 MEK 激活的药理学干预作为体内模型,以确定 ERK 在神经元活动后启动的完整转录程序。我们的调查表明,大量活性调节基因的诱导,包括 Arc/Arg3.1、Arl5b、Gadd45b、Homer1、Inhba 和 Zwint,确实依赖于 ERK 磷酸化。相比之下,一小部分基因的表达,包括 Npas4、Arl4d、Errfi1 和 Rgs2,仅部分依赖或完全独立(Ppp1r15a)于该信号通路。在鉴定的转录本中包括长非编码(lnc)RNA,并且 LincPint 和 NEAT1 的剪接变体的诱导是 ERK 依赖性的。我们的调查提供了 ERK 信号在海马体中传递的转录组反应的全面分析。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1b56/5368636/52c534e6fed4/srep45101-f1.jpg

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