SIMIAN-VIRUS-40 T-ANTIGEN-INDUCED AMPLIFICATION OF PRE-PARIETAL CELLSIN TRANSGENIC MICE - EFFECTS ON OTHER GASTRIC EPITHELIAL CELL LINEAGES AND EVIDENCE FOR A P53-INDEPENDENT APOPTOTIC MECHANISM THAT OPERATESIN A COMMITTED PROGENITOR

Gastric units in the glandular epithelium of the mouse stomach contain several types of continuously renewing epithelial cells. Acid-produci ng parietal cells are derived from a multipotent stem cell that also g ives rise to mucus producing pits cells and pepsinogen- and intrinsic factor-producing zymogenic cells. We used nucleotides -1035 to +24 of the mouse H+/K+-ATPase beta subunit gene (H+/K+-ATPase beta subunit (- 1035) (to) (+24)) to examine the consequences of expressing simian vir us 40 T antigen (SV 40 TAg) in the normally rare, nonproliferating, sh ort-lived pre-parietal cell progenitor. Light and electron microscopic morphologic studies plus multilabel immunohistochemical analyses of p ostnatal day (P) 14-80-day transgenic mice revealed that SV 40 TAg pro duces a 50-70-fold amplification of pre-parietal cells which become th e predominant cell type in gastric units. Differentiation to mature pa rietal cells is blocked, resulting in hypochlorhydria and an associate d systemic iron deficiency. SV 40 TAg-induced pre-parietal proliferati on is accompanied by apoptosis. Examination of adult transgenic mice h omozygous for p53 wild type or p53 null alleles established that the a poptosis occurs through a p53-independent pathway. H+/K+-ATPase beta s ubunit(-1035) (to) (+24)/SV40 Tag is not expressed during differentiat ion of the zymogenic lineage. Nonetheless, P28-P80 transgenic mice exh ibit an apparent block in the conversion of pre-zymogenic to zymogenic cells. This neck to neck cells and neck to pre-zymogenic cells is not affected. Comparison of normal and transgenic mice that are p53(+/+) or p53(-/-) confirmed that the loss of mature zymogenic cells is not d ependent upon p53. Although H+/K+-ATPase beta subunit-(-1035) (to) (+2 4) is not active in pit cell progenitors or their differentiated desce ndants, there is a 2-3-fold increase in mature pit cells in transgenic animals. Our findings (i) demonstrate an approach for amplifying and characterizing pre-parietal or other progenitor cell populations in ga stric units, (ii) reveal an SV 40 Tag-inducible, p53-independent apopt otic mechanism that operates in a committed epithelial progenitor cell , and (ii) provide a transgenic mouse model for defining factors that may mediate progression through specific points in the differentiation programs of the parietal and zymogenic cell lineages or that may infl uence decisions about allocation to the pit cell lineage.