Mice with a Targeted Disruption of the AE2 Exchanger Are Achlorhydric

Abstract The AE2 exchanger is expressed in numerous cell types, including epithelial cells of the kidney, respiratory tract, and alimentary tract. In gastric epithelia, AE2 is particularly abundant in parietal cells, where it may be the predominant mechanism for efflux and Cl- influx across the basolateral membrane that is needed for acid secretion. To investigate the hypothesis that AE2 is critical for parietal cell function and to assess its importance in other tissues, homozygous null mutant (AE2-/-) mice were prepared by targeted disruption of the AE2 (Slc4a2) gene. AE2-/- mice were emaciated, edentulous (toothless), and exhibited severe growth retardation, and most of them died around the time of weaning. AE2-/- mice exhibited achlorhydria, and histological studies revealed abnormalities of the gastric epithelium, including moderate dilation of the gastric gland lumens and a reduction in the number of parietal cells. There was little evidence, however, that parietal cell viability was impaired. Ultrastructural analysis of AE2-/- gastric mucosa revealed abnormal parietal cell structure, with severely impaired development of secretory canaliculi and few tubulovesicles but normal apical microvilli. These results demonstrate that AE2 is essential for gastric acid secretion and for normal development of secretory canalicular and tubulovesicular membranes in mouse parietal cells.

[1]  D. Drenckhahn,et al.  Basolateral localization of anion exchanger 2 (AE2) and actin in acid-secreting (parietal) cells of the human stomach , 1994, Histochemistry.

[2]  M. Romero,et al.  The SLC4 family of HCO3− transporters , 2004, Pflügers Archiv.

[3]  P. Bosma,et al.  Anion exchanger 2 is essential for spermiogenesis in mice , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[4]  Xuebiao Yao,et al.  Cell biology of acid secretion by the parietal cell. , 2003, Annual review of physiology.

[5]  W. Boron,et al.  Specificity of Anion Exchange Mediated by Mouse Slc26a6* , 2002, The Journal of Biological Chemistry.

[6]  G. Shull,et al.  The unique ultrastructure of secretory membranes in gastric parietal cells depends upon the presence of H+, K+-ATPase , 2002, Cell and Tissue Research.

[7]  B. Obermaier,et al.  Differential expression and regulation of AE2 anion exchanger subtypes in rabbit parietal and mucous cells , 2001, The Journal of physiology.

[8]  A. Smolka,et al.  Location of a Cytoplasmic Epitope for Monoclonal Antibody HK 12.18 on H,K-ATPase α Subunit☆ , 2000 .

[9]  T. Doetschman,et al.  Stomachs of Mice Lacking the Gastric H,K-ATPase α-Subunit Have Achlorhydria, Abnormal Parietal Cells, and Ciliated Metaplasia* , 2000, The Journal of Biological Chemistry.

[10]  J. Cuppoletti,et al.  PKA and arachidonic acid activation of human recombinant ClC-2 chloride channels. , 2000, American journal of physiology. Cell physiology.

[11]  J. Prieto,et al.  Tissue-specific N-terminal isoforms from overlapping alternate promoters of the human AE2 anion exchanger gene. , 2000, Biochemical and biophysical research communications.

[12]  T. Doetschman,et al.  Mice Lacking the Basolateral Na-K-2Cl Cotransporter Have Impaired Epithelial Chloride Secretion and Are Profoundly Deaf* , 1999, The Journal of Biological Chemistry.

[13]  P. Gleeson,et al.  Gastric H(+),K(+)-adenosine triphosphatase beta subunit is required for normal function, development, and membrane structure of mouse parietal cells. , 1999, Gastroenterology.

[14]  J. G. Duman,et al.  Cytological transformations associated with parietal cell stimulation: critical steps in the activation cascade. , 1998, Journal of cell science.

[15]  G. Boivin,et al.  Targeted disruption of the murine Na+/H+ exchanger isoform 2 gene causes reduced viability of gastric parietal cells and loss of net acid secretion. , 1998, The Journal of clinical investigation.

[16]  D. Drenckhahn,et al.  Anion exchanger 2 (AE2) binds to erythrocyte ankyrin and is colocalized with ankyrin along the basolateral plasma membrane of human gastric parietal cells. , 1998, European journal of cell biology.

[17]  J. Prieto,et al.  Molecular cloning and characterization of the human AE2 anion exchanger (SLC4A2) gene. , 2017, Genomics.

[18]  J. Rehfeld,et al.  Abnormal gastric histology and decreased acid production in cholecystokinin-B/gastrin receptor-deficient mice. , 1997, Gastroenterology.

[19]  J. Cox,et al.  Variant AE2 Anion Exchanger Transcripts Accumulate in Multiple Cell Types in the Chicken Gastric Epithelium (*) , 1996, The Journal of Biological Chemistry.

[20]  S. Parkkila,et al.  Carbonic anhydrase in the alimentary tract. Roles of the different isozymes and salivary factors in the maintenance of optimal conditions in the gastrointestinal canal. , 1996, Scandinavian journal of gastroenterology.

[21]  G. Shull,et al.  Three N-terminal Variants of the AE2 Cl/HCO Exchanger Are Encoded by mRNAs Transcribed from Alternative Promoters (*) , 1996, The Journal of Biological Chemistry.

[22]  J. Gordon,et al.  Diphtheria Toxin-mediated Ablation of Parietal Cells in the Stomach of Transgenic Mice (*) , 1996, The Journal of Biological Chemistry.

[23]  Ian Foracs Physiology of the Gastrointestinal Tract (3rd ed) , 1995 .

[24]  S. Gullans,et al.  Role of basolateral Na(+)-K(+)-Cl- cotransport in HCl secretion by amphibian gastric mucosa. , 1995, The American journal of physiology.

[25]  J. Gordon,et al.  Simian Virus 40 T Antigen-induced Amplification of Pre-parietal Cells in Transgenic Mice. , 1995, The Journal of Biological Chemistry.

[26]  M. Tohyama,et al.  The rat intrinsic factor gene: its 5'-upstream region and chief cell-specific transcription. , 1995, Journal of biochemistry.

[27]  C. Sardet,et al.  Immunolocalization of anion exchanger AE2 and cation exchanger NHE-1 in distinct adjacent cells of gastric mucosa. , 1994, The American journal of physiology.

[28]  J. Gordon,et al.  Use of transgenic mice to study regulation of gene expression in the parietal cell lineage of gastric units. , 1993, The Journal of biological chemistry.

[29]  A. Allen,et al.  Gastroduodenal mucosal protection. , 1993, Physiological reviews.

[30]  M. Tatematsu,et al.  Omeprazole, a proton pump inhibitor, reduces the secretion, synthesis and gene expression of pepsinogen in the rat stomach. , 1993, Biochemical and biophysical research communications.

[31]  S. Karam Dynamics of epithelial cells in the corpus of the mouse stomach. IV. Bidirectional migration of parietal cells ending in their gradual degeneration and loss , 1993, The Anatomical record.

[32]  S. Ruetz,et al.  Functional activation of plasma membrane anion exchangers occurs in a pre-Golgi compartment , 1993, The Journal of cell biology.

[33]  K. Watanabe,et al.  Effects of drugs acting on Cl(-)-HCO3- and Na(+)-H+ exchangers on acid secretion in the rat gastric mucosa sheet preparation. , 1992, European journal of pharmacology.

[34]  T. Machen,et al.  Regulation of Cl/HCO3 exchange in gastric parietal cells. , 1991, Cell regulation.

[35]  A. M. Paradiso,et al.  Regulation of intracellular pH in resting and in stimulated parietal cells. , 1989, The American journal of physiology.

[36]  G. Sachs,et al.  Activation of the Na+/H+ and Cl-/HCO3- exchange by stimulation of acid secretion in the parietal cell. , 1988, The Journal of biological chemistry.

[37]  G. Sachs,et al.  Electrolyte transport across the basolateral membrane of the parietal cells. , 1985, The Journal of biological chemistry.