Enterochromaffin-like (ECL) cell hyperplasia in transgenic mice with circulating progastrin but not amidated gastrin

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University of Central Lancashire / University of Liverpool (2002) J Physiol 543P, S192

Communications: Enterochromaffin-like (ECL) cell hyperplasia in transgenic mice with circulating progastrin but not amidated gastrin

C.M. Kirton*, J. Henry†, T.C. Wang‡, A. Varro, R. Dimaline and G.J. Dockray

Departments of *Physiology and †Veterinary Preclinical Science, University of Liverpool, Liverpool L69 3BX, UK and ‡Department of Gastroenterology, University of Massachussetts Medical Center, Worcester, MA, USA

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Multiple biologically active peptides are generated from the precursor of the gastric hormone gastrin (Dockray et al. 2001). In particular, the precursor peptide, progastrin, has proliferative effects that are distinct from those of the well-known acid-stimulating, COOH-terminally amidated gastrins (Wang et al. 1996).

In order to study the effects of progastrin in vivo, independently of the other gastrins, we crossed mice over-expressing a human progastrin transgene, hGas mice (Wang et al. 1996), with mice in which the wild-type gastrin gene had been deleted by homologous recombination, Gas-Ko mice (Koh et al. 1997). Off-spring were back-crossed into Gas-Ko mice for at least three generations, selecting for animals that were -/- for the wild-type gene, and +/- for the progastrin transgene, i.e. hGas X Gas-Ko mice. Animals were humanely killed where appropriate.

Plasma concentrations of amidated gastrin determined by radioimmunoassay were below the limit of detection in hGas X Gas-Ko mice and control litter mates (hGas -/-) (< 10 pM). In contrast, plasma progastrin concentrations were 560 ± 150 pM (mean ± S.E.M., n = 27) in hGas X Gas-Ko mice compared with undetectable (< 100 pM) in control litter mates. Immunocytochemistry using antibodies to chromogranin A (CgA) revealed an approximately 3-fold increase in positive cells in hGas X Gas-Ko mice (19 ± 4 cells per mm horizontal to the gland axis, n = 3) compared with control litter mates (7 ± 3; P < 0.05, unpaired t test). In EM-immunogold studies, these antibodies labelled secretory vesicles in cells with the morphology of ECL cells. In contrast, the abundance of two other endocrine cell populations, D- and X-cells (marked by somatostatin and ghrelin, respectively), was not different from controls. Intragastric pH in both hGas X Gas-Ko mice (4.9 ± 0.2, n = 6) and their control litter mates (4.3 ± 0.1), was significantly higher than in wild-type mice (2.6 ± 0.2; P < 0.05).

Thus ECL cell hyperplasia can be associated with increased circulating progastrin in the absence of amidated gastrin. The cellular mechanisms and possible interactions between progastrin and other gastrins remain to be elucidated.

All procedures accord with current UK legislation.

Where applicable, experiments conform with Society ethical requirements.

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