Stimulus-specific combinatorial functionality of neuronal c-fos enhancers

Jae Yeol Joo, Katie Schaukowitch, Lukas Farbiak, Gokhul Kilaru, Tae Kyung Kim

Research output: Contribution to journalArticlepeer-review

133 Scopus citations


The c-fos gene (also known as Fos) is induced by a broad range of stimuli and is a reliable marker for neural activity. Its induction mechanism and available reporter mouse lines are based exclusively on c-fos promoter activity. Here we demonstrate that multiple enhancers surrounding the c-fos gene are crucial for ensuring robust c-fos response to various stimuli. Membrane depolarization, brain-derived neurotrophic factor (BDNF) and forskolin activate distinct subsets of the enhancers to induce c-fos transcription in neurons, suggesting that stimulus-specific combinatorial activation of multiple enhancers underlies the broad inducibility of the c-fos gene. Accordingly, the functional requirement of key transcription factors varies depending on the type of stimulation. Combinatorial enhancer activation also occurs in the brain. Providing a comprehensive picture of the c-fos induction mechanism beyond the minimal promoter, our study should help in understanding the physiological nature of c-fos induction in relation to neural activity and plasticity.

Original languageEnglish (US)
Pages (from-to)75-83
Number of pages9
JournalNature neuroscience
Issue number1
StatePublished - Dec 29 2015

ASJC Scopus subject areas

  • Neuroscience(all)


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