The serum response factor and a putative novel transcription factor regulate expression of the immediate-early gene Arc/Arg3.1 in neurons.
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 approximately 6.5 kb and approximately 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.
Pintchovski
Sean A
SA
Gladstone Institute of Neurological Disease, San Francisco, California 94158, USA.
Peebles
Carol L
CL
Kim
Hong Joo
HJ
Verdin
Eric
E
Finkbeiner
Steven
S
D000818:Animals; D001483:Base Sequence; D002478:Cells, Cultured; D003598:Cytoskeletal Proteins / Q000096:biosynthesis* / Q000235:genetics* / Q000502:physiology; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D017874:Immediate-Early Proteins / Q000096:biosynthesis* / Q000235:genetics* / Q000502:physiology; D051379:Mice; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000096:biosynthesis* / Q000235:genetics* / Q000502:physiology; D009473:Neuronal Plasticity / Q000235:genetics; D009474:Neurons / Q000378:metabolism*; D016716:PC12 Cells; D051381:Rats; D026362:Serum Response Factor / Q000502:physiology*; D014157:Transcription Factors / Q000502:physiology*
D003598:Cytoskeletal Proteins; D017874:Immediate-Early Proteins; D009419:Nerve Tissue Proteins; D026362:Serum Response Factor; D014157:Transcription Factors; C092069:activity regulated cytoskeletal-associated protein