NFAT-3 is a transcriptional repressor of the growth-associated protein 43 during neuronal maturation

J Biol Chem. 2009 Jul 10;284(28):18816-23. doi: 10.1074/jbc.M109.015719. Epub 2009 May 14.


Transcription is essential for neurite and axon outgrowth during development. Recent work points to the involvement of nuclear factor of activated T cells (NFAT) in the regulation of genes important for axon growth and guidance. However, NFAT has not been reported to directly control the transcription of axon outgrowth-related genes. To identify transcriptional targets, we performed an in silico promoter analysis and found a putative NFAT site within the GAP-43 promoter. Using in vitro and in vivo experiments, we demonstrated that NFAT-3 regulates GAP-43, but unexpectedly, does not promote but represses the expression of GAP-43 in neurons and in the developing brain. Specifically, in neuron-like PC-12 cells and in cultured cortical neurons, the overexpression of NFAT-3 represses GAP-43 activation mediated by neurotrophin signaling. Using chromatin immunoprecipitation assays, we also show that prior to neurotrophin activation, endogenous NFAT-3 occupies the GAP-43 promoter in PC-12 cells, in cultured neurons, and in the mouse brain. Finally, we observe that NFAT-3 is required to repress the physiological expression of GAP-43 and other pro-axon outgrowth genes in specific developmental windows in the mouse brain. Taken together, our data reveal an unexpected role for NFAT-3 as a direct transcriptional repressor of GAP-43 expression and suggest a more general role for NFAT-3 in the control of the neuronal outgrowth program.

Publication types

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

MeSH terms

  • Animals
  • Binding Sites
  • Brain / embryology
  • Brain / metabolism
  • Cell Differentiation
  • Cell Line, Tumor
  • Cell Nucleus / metabolism
  • GAP-43 Protein / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • NFATC Transcription Factors / metabolism
  • NFATC Transcription Factors / physiology*
  • Neurons / metabolism
  • Neurons / pathology*
  • PC12 Cells
  • Rats
  • Rats, Sprague-Dawley
  • Signal Transduction
  • Transcription, Genetic*


  • GAP-43 Protein
  • NFATC Transcription Factors