USE OF TRANSGENIC MICE TO STUDY REGULATION OF GENE-EXPRESSION IN THE PARIETAL-CELL LINEAGE OF GASTRIC UNITS

The mechanisms that regulate cell lineage-specific and differentiation -dependent patterns of gene expression in the gastric units of the sto mach are largely unknown. Transgenic mice were generated in order to i dentify cis-acting sequences that determine the zymogenic cell-specifi c pattern of expression of the mouse intrinsic factor (InF) gene and t he parietal cell-specific pattern of expression of the mouse H+/K+-ATP ase beta-subunit gene. Portions of the 5'-nontranscribed domains of ea ch gene were linked to the human growth hormone (hGH) gene beginning a t its nucleotide +3. RNA blot hybridization studies combined with mult ilabel immunocytochemical surveys using a panel of lineage-specific an tibodies and lectins indicated that nucleotides -1035 to +24 of the mo use H+/K+-ATPase beta-subunit gene direct a pattern of reporter produc tion which recapitulates the parietal cell-specific and developmental patterns of expression of the endogenous gene. Analysis of three mosai c founders containing H+/K+-ATPase beta-subunit -1035 to +24/hGH+3 rev ealed that they had monophenotypic gastric units: a given unit contain ed either a wholly hGH-positive or a wholly hGH-negative population of parietal cells. These latter findings provide very strong evidence th at gastric units are monoclonal, i.e. they are supplied by stem cells having one genotype. Although some, but not all, parietal cells are ap parently derived from the same committed progenitor as zymogenic cells , virtually all parietal cells in a given gastric unit, but none of it s zymogenic cells, express InF-1029 to +55/hGH+3. This suggests that I nF-1029 to +55 may contain cis-acting sequences which allow parietal c ell expression in other species (e.g. humans) but lack additional elem ents which normally function in mice to suppress InF expression in thi s lineage. The absence of hGH in zymogenic cells also means that the t ranscriptional regulatory environments of parietal and zymogenic cells derived from the same precursor are distinguishable by InF-1029 to +5 5. H+/K-ATPase beta-subunit-1035 to +24 and InF-1029 to +55 are the on ly two sequences reported to date that are able to direct foreign gene expression exclusively to a gastric epithelial cell lineage in transg enic mice. This ability to deliver gene products to parietal cells can now be exploited to identify factors that control their normal prolif eration and differentiation programs and/or to specifically alter thei r biological properties.