Involvement of Nurr1 in specifying the neurotransmitter identity of ventral midbrain dopaminergic neurons.
The mesencephalic dopaminergic (mesDA) system is involved in many brain functions including motor control and motivated behaviour, and is of clinical importance because of its implication in psychiatric disorders and Parkinson's disease. Nurr1, a member of the nuclear hormone receptor superfamily of transcription factors, is essential for establishing the dopaminergic phenotype, because expression of tyrosine hydroxylase (TH), the rate-limiting enzyme in dopamine synthesis, requires Nurr1. In addition, Nurr1 plays an important role in the maintenance of mesDA neurons. Neonatal Nurr1 knockout mice lack expression of the dopamine transporter (DAT), the vesicular monoamine transporter 2 (VMAT2) and l-aromatic amino acid decarboxylase (AADC) in addition to TH specifically in mesDA neurons. It is unclear whether the lack of expression of these dopaminergic markers is caused by a maintenance defect or whether the induction of these markers depends on Nurr1 expression. To address this problem, the expression of DAT, VMAT2 and AADC was analysed at embryonic day 12.5 and 14.5. Here we demonstrate that induction of VMAT2 and DAT specifically in mesDA neurons requires Nurr1 expression, whereas AADC expression in mesDA neurons is induced independently of Nurr1 function.
Smits
Simone M
SM
Rudolf Magnus Institute of Neuroscience, Department of Pharmacology and Anatomy, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG Utrecht, The Netherlands.
Ponnio
Tiia
T
Conneely
Orla M
OM
Burbach
J Peter H
JP
Smidt
Marten P
MP
D000818:Animals; D000831:Animals, Newborn; D001142:Aromatic-L-Amino-Acid Decarboxylases / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000378:metabolism; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008562:Membrane Glycoproteins / Q000378:metabolism; D026901:Membrane Transport Proteins; D008636:Mesencephalon / Q000166:cytology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism*; D009479:Neuropeptides; D018377:Neurotransmitter Agents / Q000378:metabolism*; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D012333:RNA, Messenger / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D050492:Vesicular Biogenic Amine Transport Proteins; D050493:Vesicular Monoamine Transport Proteins
D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009479:Neuropeptides; D018377:Neurotransmitter Agents; C539883:Nr4a2 protein, mouse; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D012333:RNA, Messenger; C493453:Slc18a2 protein, mouse; D014157:Transcription Factors; D050492:Vesicular Biogenic Amine Transport Proteins; D050493:Vesicular Monoamine Transport Proteins; C433629:homeobox protein PITX3; D014446:Tyrosine 3-Monooxygenase; D001142:Aromatic-L-Amino-Acid Decarboxylases; D004298:Dopamine