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

Abstract

The enzyme tryptophan 2,3-dioxygenase [EC 1.13.11.11; L-tryptophan:oxygen 2,3-oxidoreductase (decyclizing)] first appears in the livers 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. An attempt was made to ascertain whether the appearance and development of tryptophan 2,3-dioxygenase mRNA coincided with, and thus led to, the development of enzyme activity, or whether the biosynthesis of this enzyme was due to a developmental event enabling translation of a pre-existing, sequestered, reservoir of its mRNA. Using a cell-free protein-synthesizing system based on a wheat germ S30 supernatant, the level of tryptophan 2,3-dioxygenase mRNA was measured in the livers of rats between 0 and 22 days of age. 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 postnatal day, 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 was 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. It is possible to induce tryptophan 2,3-dioxygenase catalytic activity with hydrocortisone precociously in 4-day old rats. 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 on 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 .alpha. and .beta. protomers of this enzyme.