Nurr1 regulates dopamine synthesis and storage in MN9D dopamine cells.
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.
Hermanson
Elisabet
E
Ludwig Institute for Cancer Research, Stockholm Branch, P.O. Box 240, S-171 77 Stockholm, Sweden.
Joseph
Bertrand
B
Castro
Diogo
D
Lindqvist
Eva
E
Aarnisalo
Piia
P
Wallén
Asa
A
Benoit
Gerard
G
Hengerer
Bastian
B
Olson
Lars
L
Perlmann
Thomas
T
D000818:Animals; D000900:Anti-Bacterial Agents / Q000378:metabolism; D000970:Antineoplastic Agents / Q000378:metabolism; D001142:Aromatic-L-Amino-Acid Decarboxylases / Q000235:genetics / Q000378:metabolism; D015415:Biomarkers; D002460:Cell Line; D048429:Cell Size; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism*; D004318:Doxycycline / Q000378:metabolism; D004622:Embryo, Mammalian / Q000033:anatomy & histology / Q000502:physiology; D005260:Female; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D026901:Membrane Transport Proteins; D008636:Mesencephalon / Q000166:cytology / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D009479:Neuropeptides; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D014212:Tretinoin / Q000378:metabolism; D050492:Vesicular Biogenic Amine Transport Proteins; D050493:Vesicular Monoamine Transport Proteins
D000900:Anti-Bacterial Agents; D000970:Antineoplastic Agents; D015415:Biomarkers; D004268:DNA-Binding Proteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009479:Neuropeptides; C539883:Nr4a2 protein, mouse; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; C493453:Slc18a2 protein, mouse; D014157:Transcription Factors; D050492:Vesicular Biogenic Amine Transport Proteins; D050493:Vesicular Monoamine Transport Proteins; D014212:Tretinoin; D001142:Aromatic-L-Amino-Acid Decarboxylases; D004318:Doxycycline; D004298:Dopamine