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. 1990 May 1;110(5):1791–1801. doi: 10.1083/jcb.110.5.1791

Mapping enteroendocrine cell populations in transgenic mice reveals an unexpected degree of complexity in cellular differentiation within the gastrointestinal tract

PMCID: PMC2200181  PMID: 2186049

Abstract

The gastrointestinal tract is lined with a monolayer of cells that undergo perpetual and rapid renewal. Four principal, terminally differentiated cell types populate the monolayer, enterocytes, goblet cells, Paneth cells, and enteroendocrine cells. This epithelium exhibits complex patterns of regional differentiation, both from crypt- to-villus and from duodenum-to-colon. The "liver" fatty acid binding protein (L-FABP) gene represents a useful model for analyzing the molecular basis for intestinal epithelial differentiation since it exhibits cell-specific, region-specific, as well as developmental stage specific expression. We have previously linked portions of the 5' nontranscribed domain of the rat L-FABP gene to the human growth hormone (hGH) gene and analyzed expression of the fusion gene in adult transgenic mice. High levels of hGH expression were noted in enterocytes as well as cells that histologically resembled enteroendocrine cells. In the present study, we have used immunocytochemical techniques to map the distribution of enteroendocrine cells in the normal adult mouse gut and to characterize those that synthesize L-FABP. In addition, L-FABP/hGH fusion genes were used to identify subsets of enteroendocrine cells based on their ability to support hGH synthesis in several different pedigrees of transgenic mice. The results reveal remarkable differences in transgene expression between, and within, enteroendocrine cell populations previously classified only on the basis of their neuroendocrine products. In some cases, these differences are related to the position occupied by cells along the duodenal-to-colonic and crypt-to-villus axes of the gut. Thus, transgenes appear to be sensitive tools for examining the cellular and regional differentiation of this class of intestinal epithelial cells.

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Selected References

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  1. Alpert S., Hanahan D., Teitelman G. Hybrid insulin genes reveal a developmental lineage for pancreatic endocrine cells and imply a relationship with neurons. Cell. 1988 Apr 22;53(2):295–308. doi: 10.1016/0092-8674(88)90391-1. [DOI] [PubMed] [Google Scholar]
  2. Cheng H., Leblond C. P. Origin, differentiation and renewal of the four main epithelial cell types in the mouse small intestine. V. Unitarian Theory of the origin of the four epithelial cell types. Am J Anat. 1974 Dec;141(4):537–561. doi: 10.1002/aja.1001410407. [DOI] [PubMed] [Google Scholar]
  3. Dayal Y., DeLellis R. A., Wolfe H. J. Hyperplastic lesions of the gastrointestinal endocrine cells. Am J Surg Pathol. 1987;11 (Suppl 1):87–101. doi: 10.1097/00000478-198700111-00008. [DOI] [PubMed] [Google Scholar]
  4. Evans C. J., Erdelyi E., Weber E., Barchas J. D. Identification of pro-opiomelanocortin-derived peptides in the human adrenal medulla. Science. 1983 Sep 2;221(4614):957–960. doi: 10.1126/science.6308766. [DOI] [PubMed] [Google Scholar]
  5. Hauft S. M., Sweetser D. A., Rotwein P. S., Lajara R., Hoppe P. C., Birkenmeier E. H., Gordon J. I. A transgenic mouse model that is useful for analyzing cellular and geographic differentiation of the intestine during fetal development. J Biol Chem. 1989 May 15;264(14):8419–8429. [PubMed] [Google Scholar]
  6. Lewin K. J. The endocrine cells of the gastrointestinal tract. The normal endocrine cells and their hyperplasias. Part I. Pathol Annu. 1986;21(Pt 1):1–27. [PubMed] [Google Scholar]
  7. Lluis F., Thompson J. C. Neuroendocrine potential of the colon and rectum. Gastroenterology. 1988 Mar;94(3):832–844. doi: 10.1016/0016-5085(88)90262-4. [DOI] [PubMed] [Google Scholar]
  8. McKeel D. W., Jr, Askin F. B. Ectopic hypophyseal hormonal cells in benign cystic teratoma of the ovary. Light microscopic histochemical dye staining and immunoperoxidase cytochemistry. Arch Pathol Lab Med. 1978 Mar;102(3):122–128. [PubMed] [Google Scholar]
  9. Ponder B. A., Schmidt G. H., Wilkinson M. M., Wood M. J., Monk M., Reid A. Derivation of mouse intestinal crypts from single progenitor cells. Nature. 1985 Feb 21;313(6004):689–691. doi: 10.1038/313689a0. [DOI] [PubMed] [Google Scholar]
  10. Rombout J. H., van der Grinten C. P., Binkhorst F. M., Taverne-Thiele J. J., Schooneveld H. Immunocytochemical identification and localization of peptide hormones in the gastro-entero-pancreatic (GEP) endocrine system of the mouse and a stomachless fish, Barbus conchonius. Histochemistry. 1986;84(4-6):471–483. doi: 10.1007/BF00482980. [DOI] [PubMed] [Google Scholar]
  11. Roth K. A., Lorenz R. G., McKeel D. W., Leykam J., Barchas J. D., Tyler A. N. Methionine-enkephalin and thyrotropin-stimulating hormone are intimately related in the human anterior pituitary. J Clin Endocrinol Metab. 1988 Apr;66(4):804–810. doi: 10.1210/jcem-66-4-804. [DOI] [PubMed] [Google Scholar]
  12. Roth K. A., Weber E., Barchas J. D., Chang D., Chang J. K. Immunoreactive dynorphin-(1-8) and corticotropin- releasing factor in subpopulation of hypothalamic neurons. Science. 1983 Jan 14;219(4581):189–191. doi: 10.1126/science.6129700. [DOI] [PubMed] [Google Scholar]
  13. Roth K. A., Weber E., Barchas J. D. Distribution of gastrin releasing peptide--bombesin-like immunostaining in rat brain. Brain Res. 1982 Nov 18;251(2):277–282. doi: 10.1016/0006-8993(82)90744-2. [DOI] [PubMed] [Google Scholar]
  14. Rubin D. C., Ong D. E., Gordon J. I. Cellular differentiation in the emerging fetal rat small intestinal epithelium: mosaic patterns of gene expression. Proc Natl Acad Sci U S A. 1989 Feb;86(4):1278–1282. doi: 10.1073/pnas.86.4.1278. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Schmidt G. H., Wilkinson M. M., Ponder B. A. Cell migration pathway in the intestinal epithelium: an in situ marker system using mouse aggregation chimeras. Cell. 1985 Feb;40(2):425–429. doi: 10.1016/0092-8674(85)90156-4. [DOI] [PubMed] [Google Scholar]
  16. Scopsi L., Larsson L. I. Increased sensitivity in immunocytochemistry. Effects of double application of antibodies and of silver intensification on immunogold and peroxidase-antiperoxidase staining techniques. Histochemistry. 1985;82(4):321–329. doi: 10.1007/BF00494060. [DOI] [PubMed] [Google Scholar]
  17. Seeburg P. H. The human growth hormone gene family: nucleotide sequences show recent divergence and predict a new polypeptide hormone. DNA. 1982;1(3):239–249. doi: 10.1089/dna.1.1982.1.239. [DOI] [PubMed] [Google Scholar]
  18. Sjölund K., Sandén G., Håkanson R., Sundler F. Endocrine cells in human intestine: an immunocytochemical study. Gastroenterology. 1983 Nov;85(5):1120–1130. [PubMed] [Google Scholar]
  19. Sternberger L. A., Joseph S. A. The unlabeled antibody method. Contrasting color staining of paired pituitary hormones without antibody removal. J Histochem Cytochem. 1979 Nov;27(11):1424–1429. doi: 10.1177/27.11.92498. [DOI] [PubMed] [Google Scholar]
  20. Sweetser D. A., Birkenmeier E. H., Hoppe P. C., McKeel D. W., Gordon J. I. Mechanisms underlying generation of gradients in gene expression within the intestine: an analysis using transgenic mice containing fatty acid binding protein-human growth hormone fusion genes. Genes Dev. 1988 Oct;2(10):1318–1332. doi: 10.1101/gad.2.10.1318. [DOI] [PubMed] [Google Scholar]
  21. Sweetser D. A., Birkenmeier E. H., Klisak I. J., Zollman S., Sparkes R. S., Mohandas T., Lusis A. J., Gordon J. I. The human and rodent intestinal fatty acid binding protein genes. A comparative analysis of their structure, expression, and linkage relationships. J Biol Chem. 1987 Nov 25;262(33):16060–16071. [PubMed] [Google Scholar]
  22. Sweetser D. A., Hauft S. M., Hoppe P. C., Birkenmeier E. H., Gordon J. I. Transgenic mice containing intestinal fatty acid-binding protein-human growth hormone fusion genes exhibit correct regional and cell-specific expression of the reporter gene in their small intestine. Proc Natl Acad Sci U S A. 1988 Dec;85(24):9611–9615. doi: 10.1073/pnas.85.24.9611. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Sweetser D. A., Lowe J. B., Gordon J. I. The nucleotide sequence of the rat liver fatty acid-binding protein gene. Evidence that exon 1 encodes an oligopeptide domain shared by a family of proteins which bind hydrophobic ligands. J Biol Chem. 1986 Apr 25;261(12):5553–5561. [PubMed] [Google Scholar]
  24. Trahair J. F., Neutra M. R., Gordon J. I. Use of transgenic mice to study the routing of secretory proteins in intestinal epithelial cells: analysis of human growth hormone compartmentalization as a function of cell type and differentiation. J Cell Biol. 1989 Dec;109(6 Pt 2):3231–3242. doi: 10.1083/jcb.109.6.3231. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Vaillant C., Bu'lock A., Dimaline R., Dockray G. J. Distribution and development of peptidergic nerves and gut endocrine cells in mice with congenital aganglionic colon, and their normal littermates. Gastroenterology. 1982 Feb;82(2):291–300. [PubMed] [Google Scholar]

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