CELL-TYPE-SPECIFIC GENE-EXPRESSION IN THE NEUROENDOCRINE SYSTEM - A NEUROENDOCRINE-SPECIFIC REGULATORY ELEMENT IN THE PROMOTER OF CHROMOGRANIN-A, A UBIQUITOUS SECRETORY GRANULE CORE PROTEIN

The acidic secretory protein chromogranin A universally occurs in amin e and peptide hormone and neurotransmitter storage granules throughout the neuroendocrine system. What factors govern the activity of the ch romogranin A gene, to yield such a widespread yet neuroendocrine-selec tive pattern of expression? To address this question, we isolated the mouse chromogranin A gene promoter. The promoter conferred cell type-s pecific expression in several neuroendocrine cell types (adrenal medul lary chromaffin cells, anterior pituitary corticotropes, and anterior pituitary somatolactotropes) but not in control (fibroblast or kidney) cells. In neuroendocrine cells, analysis of promoter deletions establ ished both positive and negative transcriptional regulatory domains, A distal positive domain (-4.8/-2.2 kbp) was discovered, as well as neg ative (-258/-181 bp) and positive (-147/-61 bp) domains in the proxima te promoter. The proximate promoter contained a minimal neuroendocrine -specific element between -77 and -61 bp. Sequence alignment of the mo use promoter with corresponding regions in rat and bovine clones indic ated that the mouse sequence shares over 85% homology with rat and 52% with bovine promoters. DNaseI footprinting and electrophoretic gel mo bility shift assays demonstrated the presence of nuclear factors in ne uroendocrine cells that recognized the proximate promoter. We conclude that the chromogranin A promoter contains both positive and negative domains governing its cell type-specific pattern of transcription and that a small proximate region of the promoter, containing novel as wel l as previously described elements, interacts specifically with neuroe ndocrine nuclear proteins, and is thereby sufficient to ensure widespr ead neuroendocrine expression of the gene.