Pitx3 activates mouse tyrosine hydroxylase promoter via a high-affinity binding site

Tyrosine hydroxylase (TH) is the rate-limiting enzyme of dopamine and (nor) adrenaline biosynthesis. Regulation of its gene expression is complex and d ifferent regulatory mechanisms appear to be operative in various neuronal l ineages. Pitx3, a homeodomain-containing transcription factor, has been clo ned from neuronal tissues and, in the CNS, mouse Pitx3 is exclusively expre ssed in midbrain dopaminergic (MesDA) neurons from embryonic day 11 (Ell). TH appears in these neurons at E11.5, consistent with a putative role of Pi tx3 in TH transcription. We show that Pitx3 activates the TH promoter throu gh direct interaction with a single high-affinity binding site within the p romoter and that this site is sufficient for Pitx3 responsiveness. In contr ast, we did not observe an effect of Nurr1, an orphan nuclear receptor esse ntial for normal development of MesDA neurons, on TH promoter activity. Pit x3 activation of TH promoter activity appears to be cell-dependent suggesti ng that Pitx3 action may be modulated by other(s) regulatory mechanism(s) a nd factor(s).