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

Gastric units in the glandular epithelium of the mouse stomach contain several types of continuously renewing epithelial cells. Acid-producing parietal cells are derived from a multipotent stem cell that also gives 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 virus 40 T antigen (SV 40 TAg) in the normally rare, nonproliferating, short-lived pre-parietal cell progenitor. Light and electron microscopic morphologic studies plus multilabel immunohistochemical analyses of postnatal day (P) 14-80-day transgenic mice revealed that SV 40 TAg produces a 50-70-fold amplification of pre-parietal cells which become the predominant cell type in gastric units. Differentiation to mature parietal cells is blocked, resulting in hypochlorhydria and an associated systemic iron deficiency. SV 40 TAg-induced pre-parietal proliferation is accompanied by apoptosis. Examination of adult transgenic mice homozygous for p53 wild type or p53 null alleles established that the apoptosis occurs through a p53-independent pathway. H+/K+-ATPase beta subunit(-1035) (to) (+24)/SV40 Tag is not expressed during differentiation of the zymogenic lineage. Nonetheless, P28-P80 transgenic mice exhibit 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 dependent upon p53. Although H+/K+-ATPase beta subunit-(-1035) (to) (+24) is not active in pit cell progenitors or their differentiated descendants, 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 gastric units, (ii) reveal an SV 40 Tag-inducible, p53-independent apoptotic 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 influence decisions about allocation to the pit cell lineage.