Studies in Transgenic Mice Reveal Potential Relationships between Secretin-producing Cells and Other Endocrine Cell Types

doi:10.1074/jbc.270.2.885

Studies in Transgenic Mice Reveal Potential Relationships between Secretin-producing Cells and Other Endocrine Cell Types (*)

From the Division of Gastroenterology, New England Medical Center, Tufts University School of Medicine, Boston, Massachusetts 02111

↵^§ Present address: Pediatric Gastroenterology, University of Texas Southwestern Medical School, Dallas, TX 75235.

** To whom correspondence should be addressed:
Div. of Gastroenterology, #218, New England Medical Center, 750 Washington St., Boston, MA 02111.
Tel.: 617-636-8336; Fax: 617-636-4207.

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 pancreas. 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 β cells.

Footnotes

↵^¶ Supported by Public Health Service Fogarty International Research Fellowship TW04781.
↵* This work was supported in part by a grant from the American Cancer Society and by grants from the National Institutes of Health (DK43673 and DK07471) and the GRASP Digestive Disease Center (DK34928). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore by hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
↵¹ The abbreviations used are:

hGH

human growth hormone

bp

base pair(s)

kb

kilobase pair(s)

IP

immunoperoxidase

IF

immunofluorescence

FITC

fluorescein isothiocyanate

e0.5

embryonic day 0.5

PGP

protein gene product

Tag

T antigen.
- Received August 12, 1994.
- Revision received October 25, 1994.