Identification and characterization of novel variants of the tryptophan 2,3-dioxygenase gene: differential regulation in the mouse nervous system during development.

Tryptophan 2,3-dioxygenase (TDO), an initial and rate-limiting enzyme for the kynurenine pathway of tryptophan (Trp) metabolism, is thought to play an important role in systemic Trp metabolism as well as in emotional and psychiatric status. In contrast to its predominant expression in the liver, expression of TDO in the brain is poorly understood. Here, we show that tdo mRNA is expressed in various nervous tissues, including the hippocampus, cerebellum, striatum and brainstem. During development, tdo mRNA was differentially regulated in brain tissues. Further, we identified two novel variants of the tdo gene, termed tdo variant1 and variant2. Similar tetramer formation and enzymatic activity were obtained when these forms were expressed in wheat germ and COS-7 cells, respectively. Quantitative real-time RT-PCR revealed that tdo variants were expressed in various nervous tissues, with high expression in the cerebellum and hippocampus, followed by the midbrain. tdo variant2 was the only variant expressed in the cerebellum from postnatal day 4 (P4) to P7, suggesting a unique role for this variant during early postnatal development. Our findings indicate that tdo and its novel variants may play an important role in not only the liver but also in local areas in developing and adult brain.