Abstract
We have produced transgenic mice expressing fusion genes consisting of 1.6 kilobase pairs of the secretin gene 5' flanking region to direct the expression of human growth hormone (hGH) or simian virus 40 large T antigen to secretin-producing cells. Analysis of different mouse tissues for hGH transcripts revealed expression in each of the major secretin-producing tissues, namely the intestine and endocrine pancrease. Multiple label immunohistochemistry demonstrated that the transgene was correctly directed to secretin cells in the intestinal tract, including a previously unrecognized population of secretin cells in the colon of adult and developing mice. In the small intestine, subpopulations of hGH-containing cells frequently coexpressed substance P, serotonin, and cholecystokinin, whereas in the colon, cells expressing hGH frequently coexpressed glucagon, peptide YY, or neurotensin. Transgenic mice expressing large T antigen in secretin cells developed poorly differentiated neuroendocrine tumors of the small intestine, well differentiated colonic tumors containing glucagon-expressing cells, and insulin-producing tumors in pancreas. These studies indicate that the major cis-regulatory sequences necessary for secretin expression in enteroendocrine cells and fetal islets are localized with 1.6 kilobase pairs of the transcriptional start site. Coexpression of reporter transgenes with several gastrointestinal hormones suggests a potential relationships between secretin cells and other enteroendocrine cell types, as well as pancreatic beta cells.
Highlights
From the Division of Gastroenterology, New England Medical Center, Tufts University School of Medicine, Boston, Massachusetts 02111
To determine whether the 1.6 kb of secretin gene 5' -flanking sequence could direct appropriate expression of the human growth hormone (hGH) reporter, we examined the distribution of hGH mRNA in adult transgenic mice
The results provide new information regarding the tissue and cell-specific regulation of secretin gene expression, potential relationships between secretin-producing cells and other endocrine cell types, and neuroendocrine tumorigenesis in the intestinal tract and pancreas
Summary
From the Division of Gastroenterology, New England Medical Center, Tufts University School of Medicine, Boston, Massachusetts 02111. Transgenic mice expressing large T antigen in secretin cells developed poorly differentiated neuroendocrine tumors of the small intestine, well differentiated colonic tumors containing glucagonexpressing cells, and insulin-producing tumors in pancreas. These studies indicate that the major cis-regulatory sequences necessary for secretin expression in enteroendocrine cells and fetal islets are localized with 1.6 kilobase pairs of the transcriptional start site. The liver fatty acid binding protein-hGH transgene was expressed in most cholecystokinin, gastric inhibitory polypeptide, secretin, and glucagon cells [12] and in 10-40% of substance P- and serotonin-producing cells [13]. These findings suggested that cells producing peptide YY, glucagon, neurotensin, and cholecystokinin represent one branch of the colonic enteroendocrine lineage, whereas cells expressing serotonin and/or substance P represent the other [14]
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