The long term goals of this proposal are the identification, isolation, and characterization of neuron-specific transcription factors that regulate neuron-specific neuropeptide gene expression in the forebrain. The hypothesis to be tested is that in the brain, neuron-specific neuropeptide gene expression is coordinately regulated by both ubiquitous and cell-specific transcription factors. The somatostatin gene will be used as a phenotypic marker of neuropeptide hormone producing cells. Using newly established neuronal cell lines derived from different regions of the forebrain, experiments are proposed to identify DNA cis-control elements that regulate neuron-specific expression of the somatostatin gene, as well as to evaluate the relative contribution of already known cis-control elements in the regulation of somatostatin gene transcription in neurons. Special attention will be paid to the isolation and cloning of cDNAs encoding forebrain-specific homeodomain proteins for three reasons: 1)Increasing evidence indicates that some homeodomain transcription factors play a role in the specification and maintenance of different phenotypes. 2) In islet cells, the SMS-UE, TAAT-1 and TAAT-2 elements bind a pancreatic-specific homeodomain transcription factor, similar to those encoded by the Hox family of genes, that seem to be important in the specification of pancreatic islet cell phenotypes defined by expression of the somatostatin gene. 3) Genes encoding Hox-like proteins present in the pancreas and other peripheral tissues are not expressed in the forebrain, and therefore it is hypothesized that these regulatory elements provide binding sites for homeodomain proteins that belong to forebrain-specific families.
