Differential expression of the rat gamma-glutamyl transpeptidase gene promoters along with differentiation of hepatoblasts into biliary or hepatocytic lineage

gamma-Glutamyl transpeptidase (GGT), a major enzyme of glutathione (GSH) ho meostasis, is often used as a biliary marker to follow the differentiation of hepatic precursor cells. The expression of the GGT gene is driven by dif ferent promoters and yields multiple mRNAs, depending on the cell type or t he stage of differentiation. In the present study, we analyzed the GGT mRNA expression pattern by quantitative reverse transcriptase-polymerase chain reaction or by in situ hybridization i) in the liver, in vivo, at early sta ges of development; ii) in oval cells, which proliferate and differentiate into hepatocytes in response to galactosamine injury in vivo; and finally, iii) during hepatoblast differentiation, in vitro. We show that GGT gene tr anscription originates from promoters P3, P4, and P5 in rat hepatic precurs or cells. Differentiation of these cells induces profound alterations in GG T gene expression, leading to extinction of promoters P4 and P5, when they differentiate into the hepatocytic pathway, and to extinction of promoters P3 and P5 when they differentiate into the biliary pathway. This diversity in GGT mRNA expression provides unique molecular probes to follow hepatic p recursor cell differentiation. Furthermore, the identification of factors g overning GGT P5 and P4 promoter expression should provide further insight i nto the molecular events that occur as the liver precursor cell differentia tes into the hepatic lineages.