THEMES
Lessons From Genetically Engineered Animal Models
III. Lessons learned from gastrin gene deletion in mice*

Karen L. Hinkle and Linda C. Samuelson

Department of Physiology, The University of Michigan, Ann Arbor, Michigan 48109-0622


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Gastrin is the principal hormonal inducer of gastric acid secretion. Chronic hypergastrinemia, leading to hypersecretion of gastric acid and increased proliferation of parietal and enterochromaffin-like (ECL) cells, has been well described. In contrast, the physiological consequences of chronic gastrin deficiency had been poorly understood until the recent genetic engineering of mouse mutants containing a gastrin gene deletion by homologous recombination in embryonic stem cells. This themes article describes the consequences of constitutive gastrin deficiency on the development and physiology of the stomach. A lack of gastrin disrupts basal gastric acid secretion and renders the acid secretory system unresponsive to acute histaminergic, cholinergic, and gastrinergic stimulation. The defect in acid secretion is greater than would have been predicted from previous studies in which gastrin action was acutely blocked. Cellular changes include thinning of the gastric mucosa in the gastrin-deficient mice, with a reduction in parietal cells and reduced expression of markers of parietal and ECL cell-differentiated functions. The results suggest that gastrin is required for the functional maturation of the acid-secretory system.

hypochlorhydria; gastrointestinal hormones; knockout mice; parietal cells; enterochromaffin-like cells


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THE IDENTIFICATION OF A factor produced in the antrum of the stomach that could stimulate gastric acid secretion was first reported in 1905 by Edkins and Cantab (10). This factor, termed gastrin, was subsequently purified and sequenced by Gregory and Tracy in 1964 (16). Extensive investigation since this time has detailed many aspects of the mechanism of gastrin release and the resultant stimulation of acid secretion. After ingestion of a meal, gastrin is released into the blood from antral G cells, and circulating gastrin stimulates parietal cells to secrete acid into the lumen of the stomach. Although gastrin is capable of stimulating parietal cells directly, it has an even greater effect by stimulating enterochromaffin-like (ECL) cells to release histamine, a potent paracrine stimulator of parietal cells (Fig. 1). Together, gastrin, histamine, and the neurotransmitter ACh are the major stimulators of acid release. There is some controversy as to whether a combination of agonists acting on the parietal cell or a single agonist given in isolation can stimulate acid secretion. The actions of gastrin in the stomach are mediated by the gastrin/CCK-B receptor, which is present on both parietal and ECL cells (43). In addition to its role in the regulation of gastric acid secretion, gastrin stimulates the growth of the oxyntic mucosa. Elevated gastrin levels increase the number of both parietal and ECL cells (8, 30), and sustained hypergastrinemia can be associated with the development of ECL cell carcinoid tumors (17). The reader can refer to several recent general reviews for an overview of gastrin, the gastrin/CCK-B receptor, and regulation of acid secretion (18, 47, 49).


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Fig. 1.   Schematic diagram of the major stimulators of gastric acid secretion. Acid secretion from the parietal cell is stimulated by gastrin, histamine, and ACh through the gastrin/CCK-B, H2, and muscarinic 3 receptors, respectively. Enterochromaffin-like (ECL) cells, which are located near the parietal cells in the gastric glands of the oxyntic mucosa, are the source of histamine. Gastrin and ACh stimulate histamine release from ECL cells as well as act directly on the parietal cell. The primary pathway for gastrin stimulation of acid secretion is thought to occur via histamine release, which is indicated by the heavier arrows.

Experimental models of both hypo- and hypergastrinemia have supported and furthered knowledge of the role of gastrin in acid secretion and growth of the gastric mucosa. However, in contrast to several naturally occurring models of chronic hypergastrinemia (12), natural models of chronic hypogastrinemia had not been described until the recent development of genetic mouse models. Experimental models of hypogastrinemia have been developed by pharmacological blocking of gastrin receptor activation (11, 38), surgical excision of the gastrin-producing portion of the stomach (1, 3), or immunoneutralization of gastrin with specific antibodies (21, 27, 33, 46). In general, these experimental models of hypogastrinemia showed a reduction of cells in the oxyntic mucosa and increased intragastric pH. Yet these models of hypogastrinemia can be limited by several factors: they do not ensure a complete loss of gastrin, may not be completely specific for gastrin, and are often limited to evaluation of acute effects in adult animals. Advances in genetic engineering in the mouse enabled the generation of new models with complete elimination of gastrin. Mutant mouse strains with a gastrin gene deletion have been generated by gene targeting in embryonic stem (ES) cells (14, 25), allowing the physiological consequences of a constitutive loss of gastrin to be evaluated. This themes article summarizes the phenotype of gastrin-deficient mice and highlights the essential role for gastrin in acid secretion.

Generation of gastrin-deficient mice. Molecular cloning experiments demonstrated that gastrin is encoded by a single gene in the mouse genome (13, 26). Disruption of this gene involved the deletion of the complete coding sequence by gene targeting in ES cells. Two different gastrin-deficient mouse strains have been produced by this approach with similar phenotypes (14, 25). In both mutant strains, the complete deletion of gastrin-coding sequences produced null mutants incapable of synthesizing gastrin mRNA or protein. Consequently, progastrin and all of its processing products are absent in the mutant mice. These novel agastrinemic mutants were examined to test whether gastrin is required for normal development and physiology.1

Because gastrin is abundantly expressed during fetal development (6) and gastrin-deficient models had not been previously described, it was unclear whether gastrin-deficient mice would be viable. The observations that homozygous gastrin-deficient mice were born in normal numbers, developed without visible abnormalities, and exhibited normal weight gain demonstrated that gastrin is not a vital hormone. In addition, both male and female gastrin-deficient mice are fertile and have a normal life span. CCK, which also binds to the gastrin receptor, does not compensate for the loss of gastrin. CCK peptide levels are not elevated in gastrin-deficient mice (14), and mice deficient in both gastrin and CCK are viable without obvious abnormalities (28).

Although viability, growth, and fertility were normal in gastrin-deficient mice, there was a major effect seen in the stomach. There was a severe reduction in gastric-acid secretion, as well as alterations in parietal and ECL cells, the two cell types primarily involved in acid secretion.

Impaired gastric acid secretion in gastrin-deficient mice. Because of the extensive body of research indicating that gastrin is a physiological regulator of acid secretion, it was expected that mice lacking gastrin would exhibit a defect in acid secretion. However, the extent of the impairment in acid secretion that was observed in the gastrin-deficient mice was not anticipated. Basal acid secretion measured in anesthetized mice was undetectable in the mutants in comparison to wild-type mice (14) (Fig. 2). Moreover, basal gastric pH in fasted gastrin-deficient mice was significantly higher (5.8 ± 0.3) than in wild-type control mice (4.2 ± 0.1) (25). Thus gastrin appears to be critical for establishing basal acid secretion. Previous studies that acutely blocked gastrin action by other methods had not shown a consistent effect on basal acid secretion. Several of these studies showed a decrease in basal acid secretion with the removal of gastrin by surgical, pharmacological, or immunologic means (3, 33, 38); however, the reduction was modest in comparison to the defect observed in the gastrin-deficient mice. The more severe effect observed in the gastrin-deficient mice suggests that gastrin is required for basal acid secretion.


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Fig. 2.   Basal acid secretion is undetectable in gastrin-deficient mice. Basal acid output was measured in anesthetized gastrin-deficient mice and wild-type controls after an overnight fast. Gastric secretions were collected over a 1-h period, and acid output (µmol H+) was quantitated by titration; n = 6 mice/group. Adapted from Friis-Hansen et al. (14).

Stimulated acid secretion was also severely impaired in gastrin-deficient mice. Friis-Hansen et al. (14) tested whether acid secretion was induced in anesthetized gastrin-deficient mice after acute treatment with gastrin, histamine, or the ACh analog carbachol. Similar to the basal secretion results, induced secretion was undetectable after stimulation with any of the three agonists. This finding was surprising, as previous experimental models in which gastrin-induced acid secretion was acutely blocked were still responsive to other agonists. For example, Lloyd et al. (33) showed that histamine and an ACh analog could overcome the block to acid secretion resulting from immunoneutralization of gastrin. Similarly, in a study by Ding and Hakanson (9), treatment with a gastrin/CCK-B receptor antagonist did not affect histamine- or ACh analog-induced responses. The lack of agonist-stimulated acid secretion in gastrin-deficient mice is unique and suggests a fundamental requirement of gastrin for acid secretion.

Whether the defect in acid secretion in the gastrin-deficient mice is due to the loss of direct gastrin stimulation of parietal cells or is due to a decrease in gastrin-mediated histamine release remains to be determined. Gastrin receptors are found on both parietal and ECL cells (Fig. 1). Gastrin or ACh stimulation of acid secretion is thought to be primarily indirect via histamine release from ECL cells, since histamine H2 receptor antagonists have been shown to substantially block the response to gastrin or ACh (4). Moreover, gastrin has been shown to regulate the function and growth of both ECL and parietal cells (47). Thus it is likely that, in addition to the loss of gastrin, histamine signaling could be impaired in the mutant mice. Indeed, gastric histamine content in gastrin-deficient mice is reduced 40% (14), and the concentration of mRNA for the histamine biosynthetic enzyme histidine decarboxylase (HDC) is also markedly reduced. Therefore, the basis for the defect in acid secretion in the gastrin-deficient mice could be multifaceted, involving gastrin signaling, histamine signaling, or both. Although gastrin and ACh primarily increase intracellular Ca2+, histamine primarily stimulates an increase in cAMP. It has yet to be resolved whether both signaling pathways need to be stimulated in the parietal cell in vivo for gastric acid secretion to occur. Certainly, the lack of response to histamine stimulation in gastrin-deficient mice suggests that either the acid secretory machinery is not fully functional or that histamine signaling alone is not sufficient to induce acid secretion. Acute studies with receptor antagonists make the latter possibility less likely.

Abnormal gastric mucosa in gastrin-deficient mice. Histological analysis of the oxyntic mucosa in gastrin-deficient mice showed a reduction in the thickness of the mucosa (25). All of the major epithelial cell types were present, including parietal cells, ECL cells, chief cells, and mucous cells; however, there were marked changes in the proportion and distribution of the various cells types. The morphological data as well as measurement of the expression of markers of parietal and ECL cell function demonstrated defects in both cell types important for acid secretion.

Immunostaining for the parietal cell marker H+-K+-ATPase showed that there were ~40% fewer cells in the mutant mice, with the most pronounced decrease in the pit region of the gastric glands. Moreover, the pattern of H+-K+-ATPase staining was changed. Instead of orderly columns of parietal cells lining the gastric glands, parietal cells in the mutant mice had a more scattered appearance, with unstained cells interspersed between stained cells. Although there was a clear decrease in the number of parietal cells, electron microscopy demonstrated normal size and morphology of the parietal cells in the gastrin-deficient mice (25). Thus morphologically mature parietal cells are formed, although they do not secrete acid.

ECL cells were also affected by the absence of gastrin, with a reduction in the levels of several markers of differentiated ECL cell function. Immunostaining for the ECL-specific marker HDC showed substantially fewer (30% of control) and lighter-stained cells in mutant mice (14). These data agree with previous studies demonstrating that HDC is transcriptionally regulated by gastrin (19). Staining with the more general neuroendocrine marker chromogranin A (CgA) also showed differences in gastrin-deficient mice, with one study reporting fewer cells (25) and the other noting no change in number but a repositioning of positive cells closer to the base of the gastric glands (14). CgA peptide and mRNA levels were also reduced two- to threefold, again supporting the conclusion that there are fewer ECL cells and/or a reduction in the expression of ECL-cell markers. These alterations support the hypothesis that histamine stimulation of parietal cells is impaired in gastrin-deficient mice.

In addition to the marked changes in the parietal and ECL cells in the gastrin-deficient mice, there were increases in the surface mucous cells in the mutant and a possible decrease in chief cells (25). Because all of the epithelial cells originate from a common stem cell (22), the data suggest that gastrin affects cell lineage decisions in the gastric mucosa. Little is known about the factors controlling the rate of cell proliferation and differentiation into the different cell lineages. Li et al. (32) described increased proliferation of preparietal cells in transgenic mice in which the parietal cells were ablated (Table 1). Gastrin was not measured in these mice, but, without mature parietal cells and no acid secretion, it is likely that they were hypergastrinemic, and thus gastrin could be responsible for the accelerated entry of progenitor cells into the parietal cell lineage.

                              
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Table 1.   Genetically engineered mouse models of gastric acid dysfunction and/or altered mucosal cell development

Repair of the acid secretory defect with gastrin replacement. The reduction in parietal cell number was modest in comparison to the impairment in acid secretion observed in the mutant. As mentioned earlier, this may suggest that the parietal cells are somehow functionally immature in the gastrin-deficient mice. It was of interest to characterize the changes induced by gastrin hormone replacement to study the mechanism(s) of gastrin-induced maturation of the acid secretory system. Measurement of acid secretion in gastrin-deficient mice treated with gastrin for 6 days using osmotic minipumps showed that the defect in acid secretion is at least partially correctable in adult mice (14). Restoration of acid secretion was paralleled by an increase in H+-K+-ATPase-positive parietal cells, although there was no increase in the total number of parietal cells. In addition, there was an increase in CgA peptide levels, suggesting repair of both parietal and ECL cells with the hormone replacement therapy. The timing of the repair suggests that the parietal cells that are already formed in the gastrin-deficient mice are able to respond to gastrin stimulation to exhibit more normal acid secretion.

Extragastric effects of gastrin deficiency. In addition to the marked changes in the stomach, there are alterations in the colon of the gastrin-deficient mouse. Although normal histologically, measurement of colonic cell proliferation demonstrated a decreased proliferation labeling index (25). Previous studies have suggested that it is not amidated gastrin but processing intermediates of gastrin that exert a trophic effect on the colonic mucosa. Both progastrin and glycine-extended gastrin have been shown to be produced in normal and cancerous colonic cells (23, 34, 37, 45), and both forms have been demonstrated to induce cell growth in vitro (2, 20, 40, 42). The observation of decreased proliferation of the colonic mucosa in gastrin-deficient mice suggests that gastrin, or one of its processing intermediates, does play a physiological role in the regulation of the growth of the colonic mucosa in vivo. Recent studies from Wang's laboratory (24) using various mouse models suggest that glycine-extended gastrin is most important for this effect, since overexpression of glycine-extended gastrin in transgenic mice resulted in a marked increase in the proliferation of the gastric mucosa.

Mouse models with defects in gastric acid secretion. Genetic engineering in the mouse has allowed the analysis of the essential function of gastrin through the characterization of mice with a constitutive deficiency in gastrin. This has given us new insight into the importance of gastrin for gastric acid secretion and the development of parietal and ECL cells. The severe impairment in acid secretion in the mutant mice was surprising, based on earlier studies of experimental models of hypogastrinemia. However, because histamine function is also compromised in the gastrin-deficient mice, the parietal cell defect could be due to a reduction in histamine in addition to the absence of gastrin. Further studies combining pharmacological and genetic approaches in this mouse model will help to resolve this issue.

The mouse is an excellent animal model to merge molecular, cellular, and integrative biology for the study of acid secretion. One strength of the mouse is the potential for genome engineering by gene targeting in ES cells or conventional transgenesis. Gene targeting allows the replacement of the normal gene with a mutant gene construct, thus allowing the analysis of loss-of-function mutations, as was the case for the gastrin-deficient strains. Conventional transgenics contain a gene construct that is randomly integrated in the mouse genome. Because the normal complement of genes in the genome is retained, this approach is only suitable for dominant phenotypes. In addition to the gastrin-deficient mice reviewed here, several other mouse mutants have been engineered with alterations in gastric acid secretion and/or the development of cells within the oxyntic mucosa (Table 1). Gastrin/CCK-B receptor mutants have a gastric phenotype similar to the gastrin-deficient mice (29, 36), confirming that gastrin action in the stomach is mediated by the gastrin/CCK-B receptor. The features shared by these mice and the gastrin-deficient mice include a thinner gastric mucosa, reduced numbers of parietal and ECL cells, and reduced acid secretion. Other mutant mouse models have provided further insight into the regulation of acid secretion, including the somatostatin receptor 2-deficient mutant, which exhibited a 10-fold increase in acid secretion (35). This result confirmed that somatostatin is important as an in vivo inhibitor of acid secretion. Some of the mutant mouse strains are more suitable for understanding lineage determination of the epithelial cell types of the oxyntic mucosa (31, 32).

Future studies will undoubtedly demonstrate the power of mouse models to sort out the complex physiology of acid secretion. The ability to completely remove one regulator or pathway can contribute to a clearer understanding of physiological processes. The analyses of gastrin-deficient mice have demonstrated that gastrin is necessary for acid secretion. It would also be of interest to create a mouse deficient in histamine signaling by genetic deletion of the H2 receptor. A model such as this would assist in testing the essential function of histamine and whether gastrin requires histamine to stimulate acid secretion.

Physiological analysis of acid secretion in the mouse has primarily relied on in vitro-intact organ system models and in vivo measurement of gastric secretion in anesthetized whole animals. The development of the mouse isolated stomach preparation allowed pharmacological studies to be carried out in vitro to help define the relative contributions of gastrin, histamine, and ACh in the regulation of acid secretion (5). In vivo analysis in anesthetized mice has become especially useful with the generation of new genetic models that remove or overexpress various regulators (Table 1). In the future, it will be advantageous to develop better cell isolation procedures for the mouse, as has been done for larger mammals, to study molecular aspects of parietal and ECL cells in genetically altered mice. The potential to engineer the mouse genome to remove or alter specific regulators makes this species an excellent model to apply molecular, cellular, and integrative approaches for the study of acid secretion.


    ACKNOWLEDGEMENTS

The generous input of Jean Lay and John Williams in the preparation of this manuscript is greatly appreciated.


    FOOTNOTES

* Third in a series of invited articles on Lessons From Genetically Engineered Animal Models.

K. L. Hinkle was supported by the Systems and Integrative Biology National Institutes of Health Training Grant. L. C. Samuelson acknowledges research support from the National Institutes of Health.

1 Results common to both studies describing the consequences of gastrin gene deletion in mice (14, 25) will not be specifically referenced. Reference to one of these two papers will highlight findings that are unique to that study.

Address for reprint requests and other correspondence: L. C. Samuelson, Dept. of Physiology, The Univ. of Michigan, Ann Arbor, MI 48109-0622 (E-mail: lcsam{at}umich.edu).


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Am J Physiol Gastroint Liver Physiol 277(3):G500-G505
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