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 l...

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Bibliographic Details
Published in:Journal of neuroscience research 2007-06, Vol.85 (8), p.1762-1773
Main Authors: Teh, Christina H.L., Loh, Chin Chieh, Lam, Kevin K.Y., Loo, Jia Min, Yan, Tie, Lim, Tit Meng
Format: Article
Language:English
Subjects:
Animals
Base Sequence
Basic Helix-Loop-Helix Transcription Factors - biosynthesis
Basic Helix-Loop-Helix Transcription Factors - physiology
Butyric Acid - pharmacology
Cell Differentiation
Cell Line
development
Dopamine - metabolism
Mesencephalon - embryology
Mesencephalon - metabolism
Mice
Molecular Sequence Data
Nerve Tissue Proteins - biosynthesis
Nerve Tissue Proteins - physiology
neuronal PAS domain protein 1
Neurons - enzymology
Neurons - metabolism
Promoter Regions, Genetic
Protein Binding
RNA, Small Interfering - genetics
transcriptional regulation
Tyrosine 3-Monooxygenase - genetics
Tyrosine 3-Monooxygenase - metabolism
tyrosine hydroxylase
Up-Regulation
ventral midbrain
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Summary: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. © 2007 Wiley‐Liss, Inc.
ISSN:0360-4012
1097-4547
DOI:10.1002/jnr.21312