NFAT-3 is a transcriptional repressor of the growth-associated protein 43 during neuronal maturation.
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.
Nguyen
Tuan
T
Laboratory for NeuroRegeneration and Repair, Department of Neurology, Hertie Institute for Clinical Brain Research, Germany.
Lindner
Ricco
R
Tedeschi
Andrea
A
Forsberg
Kirsi
K
Green
Andrew
A
Wuttke
Anja
A
Gaub
Perrine
P
Di Giovanni
Simone
S
D000818:Animals; D001665:Binding Sites; D001921:Brain / Q000196:embryology / Q000378:metabolism; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D019922:GAP-43 Protein / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D050778:NFATC Transcription Factors / Q000378:metabolism / Q000502:physiology*; D009474:Neurons / Q000378:metabolism / Q000473:pathology*; D016716:PC12 Cells; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D014158:Transcription, Genetic
D019922:GAP-43 Protein; D050778:NFATC Transcription Factors