Dopamine neurons express multiple isoforms of the nuclear receptor nurr1 with diminished transcriptional activity.
Nurr1 (NR4A2) is an orphan nuclear receptor required for the development and maintenance of the dopaminergic phenotype in neurons of the ventral midbrain. This study demonstrates that multiple splice variants of nurr1 are produced in rat and human dopamine neurons. Formed by alternative RNA splicing in exon 7, nurr1a has a truncated carboxy-terminus, nurr1b has an internal deletion in the ligand-binding domain and nurr1c, newly identified in this study, has a novel carboxy-terminus produced by a frame shift downstream of the splice junction. Alternative RNA splicing in exon 3 produces the isoform known as the transcriptionally-inducible nuclear receptor (TINUR), lacking the amino-terminus. Nurr2 and the newly identified nurr2c are produced by utilization of both exon 3 and exon 7 alternative splice sites. In rat midbrain, variants other than full-length nurr1 constitute 20-35% of NR4A2 transcripts. Transfection studies in dopaminergic SK-N-AS cells demonstrate that nurr1a, nurr1b, nurr1c and TINUR have significantly reduced transcriptional activities compared with full-length nurr1, while nurr2 and nurr2c are inactive. Furthermore, in these experiments, nurr2 and nurr2c both act as dominant negatives. Production of these nurr1 variants in vivo as demonstrated here could represent a novel regulatory mechanism of nurr1 transcriptional activity and therefore, dopaminergic phenotype.
Michelhaugh
Sharon K
SK
Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, Detroit, Michigan 48201, USA.
Vaitkevicius
Henrikas
H
Wang
Jun
J
Bouhamdan
Mohamad
M
Krieg
Alexys R
AR
Walker
Jennifer L
JL
Mendiratta
Varsha
V
Bannon
Michael J
MJ
D000818:Animals; D015152:Blotting, Northern / Q000379:methods; D001921:Brain / Q000166:cytology / Q000378:metabolism; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism*; D015536:Down-Regulation / Q000502:physiology; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D008156:Luciferases / Q000378:metabolism; D009447:Neuroblastoma; D009474:Neurons / Q000378:metabolism*; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D020033:Protein Isoforms / Q000378:metabolism; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D014157:Transcription Factors / Q000378:metabolism*; D014162:Transfection / Q000379:methods
D004268:DNA-Binding Proteins; C539882:NR4A2 protein, human; C539884:Nr4a2 protein, rat; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D020033:Protein Isoforms; D014157:Transcription Factors; D008156:Luciferases; D004298:Dopamine