Identification and functional characterization of ATF3 target genes that mediate neuronal survival

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Neuronal activity and NMDA receptor activation are critical for the survival of neurons. Although the precise mechanisms involved in this process are unknown, activity-induced nuclear calcium transients and gene expression mediated by the transcription factor CREB are important. Whole genome transcriptional profiling led to the discovery of a nuclear calcium-regulated, multi-component genomic survival program. The CREB target ATF3 plays a central role in this program; it acts as a transcriptional repressor and confers neuroprotection through down-regulation of genes. The aim of the project is to identify the ATF3 targets that mediate neuroprotection. We propose two experimental strategies: an unbiased search for ATF3 target genes as well as an analysis of the putative ATF3 target gene, Trpm7, a non-selective cation channel with a role in cell death. We will use whole genome transcriptome analysis to identify all genes regulated by ATF3 in hippocampal neurons and, using gene ontology searches, filter out those genes that have a possible role in apoptosis or survival. Expression of Trpm7 upon electrical activation of hippocampal neurons follows an expression profile consistent with it being a target of ATF3. We will investigate the regulation of all candidate target genes (including Trpm7) by nuclear calcium-CREB-ATF3 signaling and assess their role in neuronal survival in vitro and in vivo. This study may lead to the identification of novel gene targets for the development of neuroprotective therapies for neurodegenerative diseases.