The self-renewing epithelial populations present in the gastric units of the mouse stomach are descended from a multipotent stem cell and undergo an orderly migration-associated differentiation followed by apoptosis. The steady state census of the three principal cell types (acid-producing parietal cells, mucus-producing pit cells, and pepsinogen and intrinsic factor-producing zymogenic cells) is accurately controlled, despite marked differences in the rates of migration of each lineage. A transgenic mouse model has been created to define functional interrelationships between the proliferation, differentiation, and death programs of these lineages. Nucleotides -1035 to +24 of the noncatalytic subunit gene of mouse H+/K+- ATPase were used to direct expression of an attenuated diphtheria toxin A subunit in the parietal cell lineage. These transcriptional regulatory elements are not active in members of the pit and zymogenic lineages. Stomachs, prepared from postnatal day 28-80 transgenic mice and their normal littermates, were subjected to single- and multilabel immunohistochemical studies as well as qualitative and quantitative light and electron microscopic morphologic analyses. The toxin produced complete ablation of differentiated parietal cells. Loss of parietal cells was accompanied by a 5- fold increase 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 committed precursors of the pit and zymogenic lineages. Loss of mature parietal cells was also associated with (i) a block in the differentiation program of the zymogenic lineage with an accumulation of pre-neck cells and a depletion of their neck and mature zymogenic cell descendants, and (ii) an ~2-fold amplification of pit cells. These findings are consistent with the notion that epithelial homeostasis within gastric units is maintained by instructive interactions between their different cell lineages. Unlike pit and zymogenic cells, parietal cells complete their differentiation in the gastric unit's proliferative 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 modulate the migration-associated terminal differentiation programs of the pit and zymogenic lineages.