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 different regulatory mechanisms appear to be operative in various neuronal lineages. Pitx3, a homeodomain-containing transcription factor, has been cloned from neuronal tissues and, in the CNS, mouse Pitx3 is exclusively expressed in midbrain dopaminergic (MesDA) neurons from embryonic day 11 (E11). TH appears in these neurons at E11.5, consistent with a putative role of Pitx3 in TH transcription. We show that Pitx3 activates the TH promoter through direct interaction with a single high-affinity binding site within the promoter and that this site is sufficient for Pitx3 responsiveness. In contrast, we did not observe an effect of Nurr1, an orphan nuclear receptor essential for normal development of MesDA neurons, on TH promoter activity. Pitx3 activation of TH promoter activity appears to be cell-dependent suggesting that Pitx3 action may be modulated by other(s) regulatory mechanism(s) and factor(s).
Lebel
M
M
Laboratoire de Génétique Moléculaire, Institut de Recherches Cliniques de Montréal, Montréal, Québec, Canada.
Gauthier
Y
Y
Moreau
A
A
Drouin
J
J
D019943:Amino Acid Substitution; D000818:Animals; D001665:Binding Sites; D018236:Carcinoma, Embryonal / Q000473:pathology; D002460:Cell Line; D002522:Chlorocebus aethiops; D004247:DNA / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins; D004790:Enzyme Induction / Q000187:drug effects; D018398:Homeodomain Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D008636:Mesencephalon / Q000166:cytology / Q000196:embryology; D051379:Mice; D009419:Nerve Tissue Proteins / Q000502:physiology*; D009474:Neurons / Q000201:enzymology; D009687:Nuclear Proteins; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D051761:Paired Box Transcription Factors; D011333:Pro-Opiomelanocortin / Q000235:genetics; D011401:Promoter Regions, Genetic; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D014158:Transcription, Genetic; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000187:drug effects; D014446:Tyrosine 3-Monooxygenase / Q000096:biosynthesis / Q000235:genetics*; D000097577:Homeobox Protein PITX2
D004247:DNA; D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D051761:Paired Box Transcription Factors; D011333:Pro-Opiomelanocortin; D014157:Transcription Factors; D014446:Tyrosine 3-Monooxygenase; D000097577:Homeobox Protein PITX2; C539883:Nr4a2 protein, mouse; C491060:Phox2a protein, mouse; C101485:homeobox protein PITX1; C433629:homeobox protein PITX3