HETEROGENEOUS HEPATOCELLULAR EXPRESSION OF GLUTAMINE-SYNTHETASE IN DEVELOPING MOUSE-LIVER AND IN TESTICULAR TRANSPLANTS OF FETAL LIVER

BACKGROUND: Glutamine synthetase is exclusively expressed in pericentral hepatocytes in mammalian liver, but its regulation mechanism is still largely unknown. EXPERIMENTAL DESIGN: Heterogeneous expression of glutamine synthetase was examined in detail during mouse liver development by immunohistochemistry and by in situ hybridization. Heterogeneous expression of this enzyme was also analyzed in immature liver fragments transplanted to an ectopic site where no portal blood flow exists. RESULTS: At 18.5 days of gestation, a random, spotty distribution of low levels of glutamine synthetase mRNA was observed all over the liver parenchyma, but the enzyme protein was not detectable immunohistochemically in the liver at any fetal stage. Glutamine synthetase and its mRNA began to be heterogeneously expressed in pericentral hepatocytes 2 to 3 days after birth, when glycogen accumulation in the liver parenchyma was rather homogeneous. In the early postnatal development, a mosaic distribution of positive and negative hepatocytes with respect to glutamine synthetase protein and mRNA was noted around the central veins. Subsequently, mRNA distribution gradually became continuous, although some hepatocytes still lacked protein, indicating partial regulation at the translational level. When fetal liver fragments that had not yet heterogeneously expressed glutamine synthetase were cultured under the testis capsule of male mice, only pericentral hepatocytes expressed this enzyme after 2 months. However, the distribution of glutamine synthetase protein- and mRNA-positive hepatocytes around the central veins was patchy rather than continuous, as in perinatal livers. CONCLUSIONS: These results support the importance of local interactions of hepatocytes with intrahepatic cell populations and/or structural elements, Furthermore, they demonstrate that the capacity for the positional expression of glutamine synthetase is already established at a fetal age before expression of glutamine synthetase can be detected.