TRANSCRIPTIONAL REGULATION OF DARPP-32 AND ARPP-21

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The phosphoproteins DARPP-32 and ARPP-21 are substrates for cyclic AMP-dependent protein kinase, and their concentration is highly enriched in the medium size spiny neurons of the basal ganglia. The long term scientific objective of this proposal is to elucidate the genetic and epigenetic factors which regulate the development of these D1-dopaminoceptive neuronal phenotypes in the nigrostriatal system, a pathway which is highly relevant to numerous neuropsychiatric diseases and pharmacotherapies. Specific experiments will determine the transcription rates of these genes in newborn and adult mice, the transcription start sites, the boundaries of the flanking regions required for cell-specific transcription, and the specific cis-regulatory DNA sequences. Oligonucleotide competition experiments will be used to determine whether DNA sequences from the two genes, bind the same nuclear proteins. Finally, epigenetic factors affecting transcription of these genes will be examined in primary dissociated cultures of mouse striatum. These experiments are expected to eventually lead to the identification of caudate-specific nuclear trans-acting factors. Close contact with experts in this new field throughout the period of this grant proposal will contribute significantly to the professional development of the candidate. In addition, collaborations arising out of this work will also introduce the candidate to the use of the transgenic mouse model, another important tool in the study of phenotypic determination in the nervous system.