期刊
JOURNAL OF NEUROSCIENCE
卷 29, 期 5, 页码 1525-1537出版社
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.5575-08.2009
关键词
plasticity; brain-derived neurotrophic factor; Zeste; serum response factor; Arc; gene transcription
资金
- National Institute of Neurological Disorders and Stroke
- National Institute of Neurological Disorders and Stroke [2NS R01 039074]
- National Institute on Aging [2P01 AG022074]
- J. David Gladstone Institutes
- NIH Extramural Research Facilities Improvement Program Project
The immediate-early effector gene Arc/Arg3.1 is robustly upregulated by synaptic activity associated with learning and memory. Here we show in primary cortical neuron culture that diverse stimuli induce Arc expression through new transcription. Searching for regulatory regions important for Arc transcription, we found nine DNaseI-sensitive nucleosome-depleted sites at this genomic locus. A reporter gene encompassing these sites responded to synaptic activity in anNMDAreceptor-dependent manner, consistent with endogenous Arc mRNA. Responsiveness mapped to two enhancer regions similar to 6.5 kb and similar to 1.4 kb upstream of Arc. We dissected these regions further and found that the proximal enhancer contains a functional and conserved Zeste-like response element that binds a putative novel nuclear protein in neurons. Therefore, activity regulates Arc transcription partly by a novel signaling pathway. We also found that the distal enhancer has a functional and highly conserved serum response element. This element binds serum response factor, which is recruited by synaptic activity to regulate Arc. Thus, Arc is the first target of serum response factor that functions at synapses to mediate plasticity.
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