Organization of the human orphan nuclear receptor Nurr1 gene.
Recent reports have revealed that Nurr1 (also known as NOT/TINUR/RNR-1/HZF-3), a member of the steroid/thyroid hormone nuclear receptor superfamily, is predominantly expressed in the midbrain; substantia nigra (SN) and ventral tegmental area (VTA). Nurr1 null mice are born lethal, lacking the midbrain dopamine (DA) neurons, suggesting that Nurr1 is essential for the development and differentiation of midbrain DA neurons. Human Nurr1 gene has been mapped on chromosome 2q22-23, which is reported to associate weakly with schizophrenia. We cloned and sequenced the human Nurr1 gene, which is approximately 8.3kb long, consisting of eight exons and seven introns. Comparisons of the human Nurr1 with the mouse Nurr1, mouse Nur77 and human NOR-1 revealed that their genomic structures were highly conserved. The 5'-flanking region of the human Nurr1 included three transcriptional regulatory elements, cAMP-response element (CRE), CArG-like element and Sp-1 site, which were surrounded by CpG island, and showed a strong homology with the mouse Nurr1. We performed a primer extension analysis using mRNA from HeLa S3 cells stimulated with phorbol 12-myristate 13-acetate (PMA), Ca2+ ionophore A23187 and cycloheximide (CHX) in order to induce the Nurr1 mRNA expression, and determined one transcription initiation site within CRE. The transient transfection assay indicates that the regulatory elements in the 5'-flanking region are robust for mitogen-induced expression of the human Nurr1. Further analysis of the polymorphism of the human Nurr1 gene may reveal the association with diseases characterized by changes of the DA system, such as Parkinson's disease and schizophrenia.
Torii
T
T
Third Department of Internal Medicine, Hiroshima University School of Medicine, 1-2-3 Kasumi, Minami-ku, Hiroshima, 7348551, Japan.
Kawarai
T
T
Nakamura
S
S
Kawakami
H
H
D001483:Base Sequence; D003001:Cloning, Molecular; D004268:DNA-Binding Proteins; D005091:Exons; D017930:Genes, Reporter; D006801:Humans; D007438:Introns; D008969:Molecular Sequence Data; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D010300:Parkinson Disease / Q000235:genetics; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D012045:Regulatory Sequences, Nucleic Acid; D015183:Restriction Mapping; D012559:Schizophrenia / Q000235:genetics; D012689:Sequence Homology, Nucleic Acid; D014157:Transcription Factors / Q000235:genetics*; D014158:Transcription, Genetic / Q000235:genetics
D004268:DNA-Binding Proteins; C539882:NR4A2 protein, human; C539883:Nr4a2 protein, mouse; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D012333:RNA, Messenger; D014157:Transcription Factors