Identification and functional characterization of ATF3 target genes that mediate neuronal survival
Final Report Abstract
Synaptic activity and the subsequent generation of calcium transients invading the nucleus are known to activate a pool of about 200 genes, among them a gene program for acquired neuroprotection, which enhances the ability of neurons to survive harmful, cell death-inducing conditions. Atf3 is among the core program of 10 synaptic activity- and nuclear calcium-regulated neuroprotective genes characterized so far. The Atf3 gene contains a canonical cyclic AMP response element (CRE) in its proximal promoter region and is a direct target of CaMKIV-CREB pathway, the prototypical nuclear calcium-induced, transcription-regulating signaling module. In hippocampal neurons, expression of Atf3 is very robustly induced (50 to 100 fold increase) upon synaptic activity and the generation of synaptic NMDA receptor-induced nuclear calcium transients. ATF3 itself is a transcription factor that through its transcription-repressing activity promotes neuronal survival both in cultured hippocampal neurons exposed to excitotoxic stimuli and "in vivo" in after kainate-induced seizures. In this project we used a transcriptome analysis and identified putative genomic targets of ATF3 that may be responsible for ATF3-mediated neuroprotection. We also tested a possible neuroprotective role of ATF3 in a mouse model of stroke. We found that indeed expression ATF3 "in vivo" using stereotactic delivery of recombinant adeno associated viruses containing an expression cassette for Atf3 led to a significant reduction of brain damage after occlusion of the middle cerebral artery in the mouse. To obtain further insight into the mechanism of neuroprotection by ATF3, we studied a possible role of ATF3 in the protection from dendritic beading. Dendritic beading refers to focal swellings of dendrites, a structural alteration of the integrity of the dendritic tree that is associated with a variety of pathological conditions including brain ischemia. Dendritic beading is responsible for the rapid loss of synaptic contacts following an excitotoxic insult, which leads to an acute failure of neuronal network function. We could show that expression of ATF3 could not prevent the acute appearance of dendritic beadings but it allowed for a post-traumatic recovery of functional integrity of the dendrites. Most importantly, this recovery restored synaptic connections and neuronal network activity. These results demonstrate that ATF3 not only protects neurons from dying but it also facilitates their functional recovery after excitotoxic damage.
Publications
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(2009) Nuclear calcium signaling controls expression of a large gene pool: identification of a gene program for acquired neuroprotection induced by synaptic activity. PLoS Genet 5: e1000604
Zhang, S.J., Zou, M., Lu, L., Lau, D., Ditzel, D.A., Delucinge-Vivier, C., Aso, Y., Descombes, P., Bading, H.
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(2011) A signaling cascade of nuclear calcium– CREB-ATF3 activated by synaptic NMDA receptors defines a gene repression module that protects against extrasynaptic NMDA receptor-induced neuronal cell death and ischemic brain damage. J. Neurosci. 31, 4978-4990
Zhang, S.J., Buchthal, B., Lau, D., Hayer, S., Dick, O., Schwaninger, M., Veltkamp, R., Zou, M., Weiss, U., Bading, H.
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(2012) Increasing levels of wildtype CREB up-regulates several activity-regulated inhibitor of death (AID) genes and promotes neuronal survival. BMC Neurosci. 13, 48
Tan, Y.-W., Zhang, S.-J., Hoffmann, T., Bading, H.
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(2014). The Nuclear Calcium Signaling Target, Activating Transcription Factor 3 (ATF3), Protects against Dendrotoxicity and Facilitates the Recovery of Synaptic Transmission after an Excitotoxic Insult. J. Biol. Chem. 289, 9970-9982
Ahlgren, H., Bas-Orth, C., Freitag, H.E., Hellwig, A., Ottersen, O.P., Bading, H.
