TRANSCRIPTIONAL MECHANISMS REGULATING ACTIVITY DEPENDENT GENE EXPRESSION

Child Health And Human Development

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Abstract

The activity-dependent processes that serve to remodel the nervous system and skeletal muscles during development, require the coupling of synaptic signals to selective changes in gene expression. This type of regulation is referred to as "activity-transcription coupling". We have used the regulation of NMDA receptors in the brain and of the genes encoding contractile proteins in muscle, as models for activity-transcription coupling. We demonstrated previously that the expression of the NR2C subunit of the NMDA receptor (NR) in cerebellum requires neural activity, as well as a trophic factor known as neuregulin. In the present studies, we provide evidence that co-signaling via these 2 receptors may occur at synapses. We found that NMDA and ErbB receptors are enriched at postsynaptic densities (PSD) where they interact with the same proteins harboring PDZ protein-protein interaction domains. The PDZ-domain proteins are important because they scaffold receptors and channels to signaling molecules, thus coupling synaptic activity to signaling cascades in the postsynaptic neurons. We have also begun to characterize the DNA regulatory sequences that regulate the NR2A subunits of the receptor during development and in response to neural activity. The slow- and fast-twitch properties of muscles are determined by cell lineage and epigenetic signals derived from motoneurons, which selectively regulate the transcription of contractile genes. To understand the signaling pathways that selectively regulate distinct muscle genes, we have identified and characterized the enhancers of the troponin I slow (TnIs) and fast (TnIf) genes. Our results suggest that a complex of transcription factors interact with these enhancers to regulate transcription. Using a yeast-1-hybrid system, we have isolated putative factors that confer muscle fiber-type-specificity. One of these factors, known as GTF-3, encondes a protein with 5-6 internal repeats that may interact with a series of transcription factors. Interestingly, the GTF-3 gene, as well another member of this gene family, is deleted in persons afflicted with the Williams-Beuren Syndrome (WBS) which results from a micro-deletion on chromosome 7q11.23. Persons with WBS are reported to have variable degrees of mental retardation, supra valvular aortic stenosis, and myopathies. Studies are in progress to understand the role of GTF-3 in the deficiencies associated with WBS.