CELL LINEAGE RELATIONSHIP IN THE STOMACH OF NORMAL AND GENETICALLY MANIPULATED MICE

The oxyntic mucosa of the mouse stomach is lined with a heterogeneous population of cells that form numerous short pits continuous with long tubular glands. Tritiated thymidine radioautography has made it possi ble to pinpoint the origin of all cell types and to follow the differe ntiation/migration of different cell lineages along the pit-gland unit . The proliferating multipotent stem cells functionally anchored in th e upper glandular region, the isthmus, give rise to three main lineage precursors: 1) pre-pit cells, which migrate upward to the pit while d ifferentiating into mucus-producing pit cells; 2) pre-neck cells, whic h migrate downward to the glandular neck while differentiating into mu cus-producing neck cells that, by approaching the glandular base, grad ually change their phenotype into pepsinogen-and intrinsic factor-prod ucing zymogenic cells; 3) pre-parietal cells, which differentiate into acid-producing parietal cells in the isthmus and then undergo bipolar migration towards the pit and the glandular base. Thus, parietal cell s are the only cells that complete their differentiation in the isthmu s and then migrate to be scattered throughout the pit-gland unit. To d etermine whether parietal cells play a role in controlling decisions a bout cell fate within the pit-gland unit, the gastric epithelium has b een examined in transgenic mice expressing the H,K-ATPase beta-subunit (-1035 to +24)/simian virus 40 large T antigen fusion gene. The blocka de in parietal cell differentiation in these mice produces an amplific ation of lineage precursors, a marked depletion of zymogenic cells and an increase in pit cell census. Ablation of parietal cells in another transgenic mouse model expressing the H,K-ATPase beta-subunit(-1035 t o +24)/diphtheria toxin fragment A fusion gene also produces amplifica tion of lineage precursors, and similar effects on zymogenic and pit c ell census. These findings strongly suggest that parietal cells produc e regulatory signals that control the cellular differentiation program of both pit and zymogenic cell lineages, and would hopefully improve our ability to identify the cellular pathways leading to malignant tra nsformation.