Abstract
Nurr1, a transcription factor belonging to the nuclear receptor family, is essential for the generation of midbrain dopamine (DA) cells during embryonic development. Nurr1 continues to be expressed in adult DA neurons but the role for Nurr1 in inducing and regulating basic dopaminergic functions such as dopamine synthesis and storage has remained unknown. We have previously used MN9D dopamine cells to analyze the role of Nurr1 and retinoids in DA cell maturation. These studies demonstrated that both Nurr1 and retinoids induce cell cycle arrest and a mature morphology. Here we used MN9D cells to investigate how Nurr1 regulates dopaminergic functions. Our results demonstrate that Nurr1, but not retinoids, increases DA content and the expression of aromatic L-amino acid decarboxylase (AADC) and vesicular monoamine transporter-2 (VMAT2) in MN9D cells. In a Nurr1-inducible cell line upregulation of VMAT2 is dependent on continuous Nurr1 expression. Moreover, AADC and VMAT2 are deregulated in midbrain DA cells of Nurr1 knockout embryos as revealed by in situ hybridization. Together, the results provide evidence indicating an instructive role for Nurr1 in controlling DA synthesis and storage.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Anti-Bacterial Agents / metabolism
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Antineoplastic Agents / metabolism
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Aromatic-L-Amino-Acid Decarboxylases / genetics
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Aromatic-L-Amino-Acid Decarboxylases / metabolism
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Biomarkers
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Cell Line
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Cell Size
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism*
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Dopamine / metabolism*
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Doxycycline / metabolism
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Embryo, Mammalian / anatomy & histology
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Embryo, Mammalian / physiology
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Female
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Male
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Membrane Glycoproteins / genetics
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Membrane Glycoproteins / metabolism
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Membrane Transport Proteins*
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Mesencephalon / cytology
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Mesencephalon / physiology
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Mice
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Mice, Knockout
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Neuropeptides*
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Nuclear Receptor Subfamily 4, Group A, Member 2
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Transcription Factors / genetics
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Transcription Factors / metabolism*
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Transfection
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Tretinoin / metabolism
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Vesicular Biogenic Amine Transport Proteins
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Vesicular Monoamine Transport Proteins
Substances
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Anti-Bacterial Agents
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Antineoplastic Agents
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Biomarkers
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DNA-Binding Proteins
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Membrane Glycoproteins
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Membrane Transport Proteins
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Neuropeptides
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Nr4a2 protein, mouse
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Nuclear Receptor Subfamily 4, Group A, Member 2
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Slc18a2 protein, mouse
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Transcription Factors
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Vesicular Biogenic Amine Transport Proteins
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Vesicular Monoamine Transport Proteins
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Tretinoin
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Aromatic-L-Amino-Acid Decarboxylases
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Doxycycline
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Dopamine