DEVELOPMENT REGULATION OF GASTRIN GENE EXPRESSION

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A number of observations suggest that gastrin may play a role in regulation pancreatic development. Gastrin is transiently expressed in the pancreas during early fetal development corresponding to a time of rapid proliferation of islet cells. In addition, pancreatic gastrin is selectively repressed after birth when the mature, pancreatic islets have little capacity for further proliferation or regeneration. Furthermore, gastrin has recently been shown to act as an autocrine growth factor in vitro for some islet cell lines. The activity of the gastrin promoter in islet cells depends on a cis-acting islet cell specific DNA element similar to the insulin enhancer. Upstream of the insulin enhancer-like element is a silencer element, identical to part of the B-interferon negative regulatory domain, to which a trans-acting repressor binds to inhibition gastrin gene transcription. In vivo competition and DNA transfection studies will be used to demonstrate that the gastrin promoter is activated in islet cells by the same islet cell specific transcription factor which activates the insulin gene. Binding of the insulin transactivator to the insulin enhancer-like element will also be shown using mobility shift assays and methylation interference studies. Gastrin transgenes containing deletions of the insulin enhancer-like domain will be inserted into the germline of mice to determine if this abolishes pancreatic expression during fetal development. Analysis of the developmental expression of gastrin transgenes containing deletions of the B-interferon-like negative element should provide insights into the role of the negative element in mediating the postnatal extinction of pancreatic gastrin expression. Further, the transgenic approach should define the role of gastrin as an islet cell growth factor. The effect of oncogenes and growth factors on repressor activity will also be investigated in order to elucidate the mechanism through which proto- oncogenes regulate islet cell differentiation. Overall, these studies on the regulation of the gastrin promoter provide an approach to analyze the molecular events that regulate islet cell differentiation. Understanding these events may lead to ways of improving islet cell regeneration.