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The Journal of Neuroscience, February 4, 2009, 29(5):1525-1537; doi:10.1523/JNEUROSCI.5575-08.2009

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Development/Plasticity/Repair
The Serum Response Factor and a Putative Novel Transcription Factor Regulate Expression of the Immediate-Early Gene Arc/Arg3.1 in Neurons

Sean A. Pintchovski,1,6 Carol L. Peebles,1,6,7 Hong Joo Kim,1 Eric Verdin,2,3 and Steven Finkbeiner1,4,5,6,7

Gladstone Institutes of 1Neurological Disease and 2Virology and Immunology, San Francisco, California 94158, and Departments of 3Medicine, 4Neurology, and 5Physiology, 6Neuroscience Graduate Program, and 7Medical Scientist Training Program, University of California, San Francisco, California 94143

Correspondence should be addressed to Steven Finkbeiner, Gladstone Institute of Neurological Disease, 1650 Owens Street, San Francisco, CA 94158. Email: sfinkbeiner{at}gladstone.ucsf.edu

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 an NMDA receptor–dependent manner, consistent with endogenous Arc mRNA. Responsiveness mapped to two enhancer regions ~6.5 kb and ~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.

Key words: plasticity; brain-derived neurotrophic factor; Zeste; serum response factor; Arc; gene transcription

Received Nov. 21, 2008; accepted Dec. 26, 2008.

Correspondence should be addressed to Steven Finkbeiner, Gladstone Institute of Neurological Disease, 1650 Owens Street, San Francisco, CA 94158. Email: sfinkbeiner{at}gladstone.ucsf.edu






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