Expression of activating transcription factor-2, serum response factor and cAMP/Ca response element binding protein in the adult rat brain following generalized seizures, nerve fibre lesion and ultraviolet irradiation

Neuroscience. 1997 Nov;81(1):199-212. doi: 10.1016/s0306-4522(97)00170-x.


The expression of the constitutive transcription factors activating transcription factor-2 (ATF-2), serum response factor (SRF) and cAMP/Ca response element binding factor (CREB), and the phosphorylation of SRF and CREB were studied in the untreated adult rat nervous system and following seizure activities and neurodegenerative stimuli. In the untreated rat, intense nuclear SRF immunoreactivity was present in the vast majority of neurons in the forebrain, cortex, striatum, amygdala and hippocampus, and in some scattered neurons in the medulla and spinal cord. In contrast, SRF immunoreactivity was absent in the midline areas of the forebrain, e.g., the globus pallidum and septum, and in the hypothalamus, thalamus, mesencephalon and motoneurons. Nuclear ATF-2 was expressed at high levels in apparently all neurons, but not glial cells, throughout the neuraxis except for those neuronal populations which exhibit a high basal level of c-Jun, i.e. dentate gyrus and the motoneurons of cranial and somatosensory neurons. CREB immunoreactivity was present at a rather uniform intensity in all neuronal and glial cells throughout the neuraxis. Two hours, but not 5 h or 24 h, following systemic application of kainic acid, an increase in SRF was detectable by western blot analysis in hippocampal and cortical homogenates whereas the expression of ATF-2 and CREB did not change. Phosphorylation of CREB at serine 133 and of SRF at serine 103 were studied with specific antisera. In untreated rats, intense phosphoCREB and phosphoSRF immunoreactivities labelled many glial cells and/or neurons with the highest levels in the dentate gyrus, the entorhinal cortex and the retrosplenial cortex. Following kainate-induced seizures, phosphoSRF-IR but not phosphoCREB-IR transiently increased between 0.5 h and 2 h. Following transection of peripheral or central nerve fibres such as optic nerve, medial forebrain bundle, vagal and facial nerve fibres, ATF-2 rapidly decreased in the axotomized neurons during that period when c-Jun was rapidly expressed. SRF remained unchanged and CREB disappeared in some axotomized subpopulations. Similar to axotomy, c-Jun increased and ATF-2 decreased in cultured adult dorsal root ganglion neurons following ultraviolet irradiation. The distribution of SRF and ATF-2 suggests that their putative target genes c-fos, junB, krox-24 and c-jun can be independently regulated from SRF and ATF-2. The suppression of ATF-2 and the expression of c-Jun following axotomy and ultraviolet irradiation might be part of a novel neuronal stress response in the brain that strongly resembles the stress response characterized in non-neuronal cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activating Transcription Factor 2
  • Age Factors
  • Animals
  • Antibody Specificity
  • Axotomy
  • Brain Chemistry / physiology*
  • Brain Chemistry / radiation effects
  • Cyclic AMP Response Element-Binding Protein / biosynthesis*
  • Cyclic AMP Response Element-Binding Protein / immunology
  • Cyclic AMP Response Element-Binding Protein / metabolism
  • DNA-Binding Proteins / biosynthesis*
  • DNA-Binding Proteins / immunology
  • DNA-Binding Proteins / metabolism
  • Epilepsy, Generalized / metabolism
  • Epilepsy, Generalized / physiopathology*
  • Excitatory Amino Acid Agonists / pharmacology
  • Kainic Acid / pharmacology
  • Leucine Zippers / immunology
  • Male
  • Nerve Degeneration / drug therapy
  • Nerve Degeneration / pathology
  • Nerve Degeneration / radiotherapy
  • Nerve Fibers / pathology
  • Nerve Fibers / radiation effects
  • Nuclear Proteins / biosynthesis*
  • Nuclear Proteins / immunology
  • Nuclear Proteins / metabolism
  • Phosphoproteins / analysis
  • Phosphoproteins / immunology
  • Phosphorylation
  • Proto-Oncogene Proteins c-jun / biosynthesis
  • Proto-Oncogene Proteins c-jun / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Serum Response Factor
  • Synaptic Transmission / drug effects
  • Synaptic Transmission / physiology
  • Transcription Factors / biosynthesis*
  • Transcription Factors / immunology
  • Transcription Factors / metabolism
  • Ultraviolet Rays


  • Activating Transcription Factor 2
  • Atf2 protein, rat
  • Cyclic AMP Response Element-Binding Protein
  • DNA-Binding Proteins
  • Excitatory Amino Acid Agonists
  • Nuclear Proteins
  • Phosphoproteins
  • Proto-Oncogene Proteins c-jun
  • Serum Response Factor
  • Transcription Factors
  • Kainic Acid