Developmental control of messenger RNA for hepatic tryptophan 2,3-dioxygenase

Abstract

The enzyme tryptophan 2,3-dioxygenase [EC 1.13.11.11; Ltryptophan:oxygen 2,3-oxidoreductase (decyclizing)] first appears in thelivers of young rats around the 15th postnatal day, and increases to the adult level by the 22nd day. Studies have shown that the appearance and subsequent development of the enzyme activity result from an increase in the rate of its synthesis and thus in the amount present in the liver. In this study, we have attempted to ascertain whether the appearance and development of tpto han 2,3-dioxygenase mRNA coincided with, and thus le to, e development of enzyme activity, or whether the biosynthesis of this enzyme was due to a developmental event enabling translation of a preexisting, sequestered, reservoir of its mRNA. Using a cell-free protein-synthesizing system based on a wheat germ S30 supernatant, we measured the level of tryptophan 2,3-dioxygenase mRNA in the livers of rats between 0 and 22 days of age. We found that functional tryptophan 2,3-dioxygenase mRNA is not detectable in rat liver until the 15th postnatal day. It increases to the adult level by the 22nd postnatalday, in parallel with the enzyme. The appearance and development of tryptophan 2,3-dioxygenase are the direct consequence of the parallel appearance and development of its mRNA.It has been shown that glucocorticoids, which induce tryptophan 2,3-dioxygenase activity in adult rats, are capable of inducing the appearance of this enzyme precociously in 8-and 10-day-old rats. We have found that it is also possible to induce tryptophan 2,3-dioxygenase catalytic activity with hydrocortisone precociously in 4-day-old rats. Moreover, precocious induction of enzyme activity and the induction that occurs during the enzyme's normal developmental rise to the adult level between 15 and 22 days, are mediated through parallel increases in the level of tryptophan 2,3-dioxygenase mRNA.The present findings indicate that glucocorticoids are developmental hormones that act upon the postnatal hepatocyte to evoke elevated levels of the mRNA species coding for tryptophan 2,3-dioxygenase; the findings are compatible with the hypothesis that such hormones act by initiating and accelerating transcription of the structural genes coding for the a and i protomers of this enzyme.One of the central questions in the study of development is the determination of the biochemical level at which the appearance of tissue-specific proteins is regulated. In certain systems, control of the appearance of some proteins is pretranslational, because evidence exists suggesting that the appearance of the proteins is immediately preceded by the appearance of their respective mRNAs. Thus, the switch from fetal to adult (FA) hemoglobin in the sheep has been attributed to changes in the cellular content of functional globin mRNAs (1). Furthermore, the glucocorticoid induction of glutamine synthetase in embryonic chick neural retina cultures results from an increased rate of synthesis of the enzyme, and requires concomitant RNA synthesis (2). However, in other...

Isolated Small Rat Hepatocytes Express both Annexin III and Terminal Differentiated Hepatocyte Markers, Tyrosine Aminotransferase and Tryptophan Oxygenase, at the mRNA Level

“…16,19,20) TO expression is also virtually absent in the fetus; the accumulation of mRNA is followed by an increase in enzyme activity 14 d after birth, when the transcription of the gene is activated. 17,18,21,22) On the other hand, albumin mRNA expression has been detected in rat embryo on gestational day 9.5-10.5. 23) Based on their characteristic expression patterns, TAT and TO are used as terminal differentiated hepatocyte markers from hepatic progenitor cells or bone marrow-derived stem cells to hepatic cells.…”