THE SPATIOTEMPORAL CONTROL OF THE EXPRESSION OF GLUTAMINE-SYNTHETASE IN THE LIVER IS MEDIATED BY ITS 5'-ENHANCER

In previous studies of the glutamine synthetase gene, the promoter and two enhancer elements, one in the upstream region and one within the first intron, were identified, To analyze the role of the far-upstream enhancer element in the regulation of the expression of the glutamine synthetase gene, two classes of transgenic mice were generated, In GS K mice, the basal promoter directs the expression of the chloramphenic ol acetyltransferase reporter gene, In GSL mice reporter gene expressi on is driven, in addition, by the upstream regulatory region, includin g the far-upstream enhancer, Whereas chloramphenicol acetyltransferase expression was barely detectable in GSK mice, high levels were detect ed in GSL mice, By comparing chloramphenicol acetyltransferase express ion with that of endogenous glutamine synthetase in GSL mice, three gr oups of organs were distinguished in which the effects of the upstream regulatory region on the expression of glutamine synthetase were quan titatively different, The chloramphenicol acetyltransferase mRNA in th e GSL mice was shown to be localized in the pericentral hepatocytes of the liver, The developmental changes in chloramphenicol acetyltransfe rase enzyme activity in the liver were similar to those in endogenous glutamine synthetase, These results show that the upstream region is a major determinant for three characteristics of glutamine synthetase e xpression: its organ specificity, its pericentral expression pattern i n the liver, and its developmental appearance in the liver.