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

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Abstract
A number of genes encoding neuropeptides are expressed in the peripheral and central nervous systems, in different endocrine organs, and in spe- cialized cells distributed along the gastrointestinal tract. Whether expression of the same neuropep- tide gene in different tissues is regulated by similar transcriptional mechanisms or by mechanisms that differ in a cell-specific manner remains un- clear. We report on promoter studies on the regu- lation of the somatostatin gene in immortalized neural precursor cells derived from developing rat forebrain. Expression of the somatostatin gene in these cells was determined by RT-PCR/Southern blot analysis, by immunocytochemistry, and by RIA. We show that in cerebrocortical and hip- pocampal 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 somatostatin 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-TAAT2, and SMS-UE, three previously identified homeodomain protein-binding regula- tory elements that enhance transcription in pan- creatic cells, act as repressors of transcription in neural cells. Electrophoretic mobility shifts assays indicate that those elements bind protein com- plexes that differ between neural and pancreatic cells. Our results support the notion that expres- sion of the somatostatin gene in neural cells oc- curs via transcriptional mechanisms that are dif- ferent from those regulating expression of the same gene in pancreatic cells. (Molecular Endocri- nology 12: 1280-1293, 1998)

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