DIFFERENTIAL REGULATION OF BASAL AND CYCLIC ADENOSINE 3',5'-MONOPHOSPHATE-INDUCED SOMATOSTATIN GENE-TRANSCRIPTION IN NEURAL CELLS BY DNA CONTROL ELEMENTS THAT BIND HOMEODOMAIN PROTEINS

A number of genes encoding neuropeptides are expressed in the peripher al and central nervous systems, in different endocrine organs, and in specialized cells distributed along the gastrointestinal tract. Whethe r expression of the same neuropeptide gene in different tissues is reg ulated by similar transcriptional mechanisms or by mechanisms that dif fer in a cell-specific manner remains unclear. We report on promoter s tudies on the regulation of the somatostatin gene in immortalized neur al precursor cells derived from developing rat forebrain. Expression o f the somatostatin gene in these cells was determined by RT-PCR/Southe rn blot analysis, by immunocytochemistry, and by RIA. We show that in cerebrocortical and hippocampal cells, expression of the somatostatin gene is regulated by several negative and positive DNA cis-regulatory elements located throughout the promoter region. The somatostatin cAMP -response element appears to play a prominent role in neural somatosta tin gene expression by acting as a strong enhancer even in the absence of cAMP stimulation. Site-directed mutagenesis followed by transient transfection assays indicated that SMS-TAAT1,SMS-TAATP, and SMS-UE, th ree previously identified homeodomain protein-binding regulatory eleme nts that enhance transcription in pancreatic cells, act as repressors of transcription in neural cells. Electrophoretic mobility shifts assa ys indicate that those elements bind protein complexes that differ bet ween neural and pancreatic cells. Our results support the notion that expression of the somatostatin gene in neural cells ocours via transcr iptional mechanisms that are different from those regulating expressio n of the same gene in pancreatic cells.