DIPHTHERIA TOXIN-MEDIATED ABLATION OF PARIETAL-CELLS IN THE STOMACH OF TRANSGENIC MICE

The self-renewing epithelial populations present in the gastric units of the mouse stomach are descended from a multipotent stem cell and un dergo an orderly migration-associated differentiation followed by apop tosis, The steady state census of the three principal cell types (acid -producing parietal cells, mucus-producing pit cells, and pepsinogen a nd intrinsic factor-producing zymogenic cells) is accurately controlle d, despite marked differences in the rates of migration of each lineag e, A transgenic mouse model has been created to define functional inte rrelationships between the proliferation, differentiation, and death p rograms of these Lineages, Nucleotides -1035 to +24 of the noncatalyti c beta subunit gene of mouse H+/K+-ATPase were used to direct expressi on of an attenuated diphtheria toxin A subunit in the parietal cell li neage, These transcriptional regulatory elements are not active in mem bers of the pit and zymogenic lineages, Stomachs, prepared from postna tal day 28-80 transgenic mice and their normal littermates, were subje cted to single- and multilabel immunohistochemical studies as well as qualitative and quantitative light and electron microscopic morphologi c analyses, The toxin produced complete ablation of differentiated par ietal cells, Loss of parietal cells was accompanied by a 5-fold increa se in the number of undifferentiated granule-free cells located in the proliferative compartment of gastric units, This amplified population of granule-free cells included the multipotent stem cell as well as c ommitted precursors of the pit and zymogenic lineages, Loss of mature parietal cells was also associated with (i) a block in the differentia tion program of the zymogenic lineage with an accumulation of pre-neck cells and a depletion of their neck and mature zymogenic cell descend ants, and (ii) an similar to 2-fold amplification of pit cells, These findings are consistent with the notion that epithelial homeostasis wi thin gastric units is maintained by instructive interactions between t heir different cell lineages, Unlike pit and zymogenic cells, parietal cells complete their differentiation in the gastric unit's proliferat ive compartment before undergoing a bipolar migration along the unit, Thus, the mature parietal cell is in a strategic position to influence decision-making among gastric epithelial cell precursors and to modul ate the migration-associated terminal differentiation programs of the pit and zymogenic lineages.