Stimulus-specific combinatorial functionality of neuronal c-fos enhancers

Nat Neurosci. 2016 Jan;19(1):75-83. doi: 10.1038/nn.4170. Epub 2015 Nov 23.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Brain / metabolism*
  • Brain-Derived Neurotrophic Factor / metabolism
  • Embryo, Mammalian
  • Enhancer Elements, Genetic*
  • Epigenesis, Genetic
  • Gene Expression*
  • Genes, fos / physiology*
  • Mice
  • Neuronal Plasticity
  • Neurons / metabolism*
  • Promoter Regions, Genetic
  • RNA, Messenger
  • Transcription, Genetic*


  • Brain-Derived Neurotrophic Factor
  • RNA, Messenger