Neuronal PAS domain protein 1 regulates tyrosine hydroxylase level in dopaminergic neurons.
Catecholamines (dopamine, norepinephrine, and epinephrine) are all synthesized from a common pathway in which tyrosine hydroxylase (TH) is the rate-limiting enzyme. Dopamine is the main neurotransmitter present in dopaminergic neurons of the ventral midbrain, where dysfunction of these neurons can lead to Parkinson's disease and schizophrenia. Neuronal PAS domain protein 1 (NPAS1) was identified as one of the genes up-regulated during dopaminergic MN9D cell differentiation. We found that there was a corresponding decrease in TH level during MN9D differentiation. Overexpression and siRNA experiments revealed that NPAS1, in concert with ARNT, negatively regulates the expression of TH and that this regulation is mediated by a direct binding of NPAS1 on the TH promoter. Expression studies also confirmed a decrease in TH level in the ventral midbrain during mouse development, concomitant with an increase in NPAS1 level. These results suggest that NPAS1 plays a novel and important role in regulating TH level of dopaminergic neurons in the ventral midbrain during development.
Teh
Christina H L
CH
Department of Biological Sciences, Faculty of Science, National University of Singapore, Singapore.
Loh
Chin Chieh
CC
Lam
Kevin K Y
KK
Loo
Jia Min
JM
Yan
Tie
T
Lim
Tit Meng
TM
D000818:Animals; D001483:Base Sequence; D051792:Basic Helix-Loop-Helix Proteins / Q000096:biosynthesis / Q000502:physiology*; D020148:Butyric Acid / Q000494:pharmacology; D002454:Cell Differentiation; D002460:Cell Line; D004298:Dopamine / Q000378:metabolism*; D008636:Mesencephalon / Q000196:embryology / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000502:physiology*; D009474:Neurons / Q000201:enzymology / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D034741:RNA, Small Interfering / Q000235:genetics; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
D051792:Basic Helix-Loop-Helix Proteins; D020148:Butyric Acid; D004298:Dopamine; D009419:Nerve Tissue Proteins; D034741:RNA, Small Interfering; D014446:Tyrosine 3-Monooxygenase; C512770:Npas1 protein, mouse