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Injury-induced NF-B activation in the hippocampus: implications for neuronal survival¹

C. A. KASSED^*, T. L. BUTLER^*, G.W. PATTON, D. D. DEMESQUITA^*, M. T. NAVIDOMSKIS^*, S. MÉMET, A. ISRAËL and K. R. PENNYPACKER^*,2

^* Department of Pharmacology and Therapeutics, and
Department of Medical Microbiology, University of South Florida, Tampa, Florida, USA; and
Unite de Biologie Moleculaire de Expression Genique, Institut Pasteur, Paris, France

²Correspondence: College of Medicine Department of Pharmacology and Therapeutics University of South Florida 12901 Bruce B. Downs Blvd. MDC 9 Tampa, FL 33612, USA. E-mail: kpennypa{at}hsc.usf.edu

SPECIFIC AIMS

This study was designed to determine 1) the activity and localization of NF-B in the mouse hippocampus after chemical-induced injury; and 2) the genes dependent on the expression of NF-B p50 subunit and chemical-induced injury using microarray analysis.

PRINCIPAL FINDINGS

1. Injury-induced NF-B activity in the mouse hippocampus is primarily localized in neurons

2. NF-B activity is significantly increased in mouse hippocampus at 4 days after injury and remains elevated until 21 days, after neurodegeneration has ceased

3. Several genes associated with cellular survival are dependent on injury and the NF-B p50 subunit
Some of the genes, such as ß-glucuronidase, are known to provide cellular protection during injury, while others, such as calcium/calmodulin protein kinase II , are upregulated to enhance neurite outgrowth

4. The Na⁺, K⁺-ATPase subunit is induced in a NF-B p50 and injury dependent manner and has not been described in the brain prior to this report

5. The promoter regions of these genes do not contain an identifiable NF-B binding site but are GC rich and do not contain a TATA box

CONCLUSIONS AND SIGNIFICANCE

This work shows that using NF-B reporter mice, this transcription factor is activated primarily in neurons after injury to the mouse hippocampus (Fig. 1 ). Gene microarray analyses were carried out comparing the induction of genes in brain injury response between nontransgenic and NF-B p50 null mice. These studies revealed several genes that are p50- and injury-dependent and most of these genes are involved in survival or repair processes (Fig. 2 ). Expression of Na⁺, K⁺ -ATPase subunit has not been described in the brain before this report and may play an important role in maintaining neuronal homeostasis after injury.

View larger version (149K): [in this window] [in a new window]   Figure 1. NF-B activity is not localized in astrocytes. Mice carrying a B-dependent lacZ reporter gene were injected with saline or 2.25 mg/kg TMT, and killed after survival times of 1 d to 28 d. Coronally sliced hippocampal sections were consecutively labeled with antibodies against ß-galactosidase (brown) and GFAP (dark gray). Basal levels of ß-galactosidase and GFAP are shown on sections from saline-treated mice (A–C) in CA4/dentate gyrus (A) and CA1 (B, C) hippocampal subregions. At the 7 d survival point, marked reactive astrogliosis is observed in the CA4/dentate gyrus (D, F) and CA1 (E) subregions, without co-localization of GFAP and ß-galactosidase. By the 28 d survival time point, GFAP still does not co-localize with ß-galactosidase in any subregion, including CA1 (G) and CA3 (H, I). Magnification X100: A, B, D, E, G, H; X400: C, F, I.

View larger version (23K): [in this window] [in a new window]   Figure 2. Expression of NF-B p50-modulated genes are increased in nontransgenic mice after TMT treatment. Microarray analysis identified fourteen genes with expression that were upregulated over 2.0 fold and three genes upregulated between 1.5- to 2-fold in nontransgenic mice seven days after TMT but did not change in NF-B p50 null mice. These genes were characterized as five functional groups.

Whether NF-B activation in neuronal response to injury is prodeath or prosurvival is controversial, and may be dependent on inducing stimulus and cell-specific expression. This study and an increasing number of others demonstrate that NF-B signaling is an important survival response in neurons. The current findings show that NF-B activity occurs during and after neurodegeneration, suggesting not only a role in survival but also in repair. Most genes identified from microarray analyses are related to survival or repair, providing further evidence that NF-B is involved in these processes after brain injury.

That genes with characterized promoter regions identified as NF-B p50 dependent do not have a recognizable NF-B regulatory site is an unresolved issue. These gene promoters also are TATA-less and GC rich promoters. How does NF-B p50 regulate these genes without the corresponding regulatory site in the promoter region? Possible NF-B sites may be located outside of the characterized promoter region or may be indirectly affected by NF-B p50.

View larger version (14K): [in this window] [in a new window]   Figure 3. Schematic diagram.

FOOTNOTES

¹ To read the full text of this article, go to http://www.fasebj.org/cgi/doi/10.1096/fj.03-0773fje; doi: 10.1096/fj.03-0773fje

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