Sensory experience influences brain development by activating neural circuits. The activation of these pathways leads to calcium-dependent regulation of various aspects of neuronal function such as synaptic plasticity, cell survival, and axonal and dendritic remodeling. In most of these instances calcium signals exert long-lasting cellular effects by activating transcription factors that induce expression of target genes. Our overall goal is to gain insight into the mechanisms by which calcium signals influence brain development via transcriptional activation. Calcium-regulated transcription factors have historically been identified based on promoter analysis of target genes, and that approach has led to the identification of functionally important transcription factors such as CREB. The promoter analysis approach, while effective, is not suited for comprehensive identification of transcription factors, especially if the target genes are not known. To identify calcium-activated transcription factors and to evaluate their role in cortical development we have developed a new screen that can be used to clone calcium-activated transcription factors in neurons without prior knowledge of the target genes. Using this screen we have identified a new transcription factor called CREST that is selectively expressed in postmitotic neurons and is activated by calcium influx.
The aims of this proposal are to characterize the molecular mechanisms that regulate CREST-mediated transcription, and to evaluate the role of CREST in cortical development and plasticity based on analysis of mice that have a targeted disruption of the CREST gene. Analysis of the CREST gene will likely provide important insight into the molecular basis of developmental neurological and psychiatric disorders such as mental retardation and learning disabilities.
