상위피인용논문
- 조회1,117
Abstract
Kwang-Soo Kim1, Chun-Hyung Kim1,†, Dong-Youn Hwang1,†, Hyemyung Seo2,†, Sangmi Chung1, Seok Jong Hong1, Jin-Kyu Lim3, Therese Anderson1,2 andOle Isacson2
1 Molecular Neurobiology Laboratory and
2 Neuroregeneration Laboratories, McLean Hospital, Harvard Medical School, Belmont, Massachusetts, USA
3 Department of Animal Science and Biotechnology, KyungBuk National University, Korea
† These authors equally contributed to this work.
*Address correspondence and reprint requests to Kwang-Soo Kim, Molecular Neurobiology Laboratory, McLean Hospital, Harvard Medical School, 115 Mill Street, Belmont, MA 02478, USA.
Abstract
Tyrosine hydroxylase (TH) catalyzes the first and rate-limiting step of catecholamine synthesis and its expression is necessary for neurotransmitter specification of all catecholaminergic neurons, while dopamine β-hydroxylase (DBH) is essential for the noradrenergic phenotype. In the present study, we show that Nurr1, an orphan nuclear receptor critical for dopaminergic (DA) neuron development, directly transactivates the promoter activity of the TH gene in a cell type-dependent manner, while it does not regulate the DBH promoter. Consistent with these results, only the TH promoter contains multiple sequence motifs homologous to the known Nurr1-binding motif, NBRE. TH promoter deletional analysis indicates that ＜1.0 kb upstream sequences, encompassing three NBRE-like motifs (i.e. NL1, NL2 and NL3) are mostly responsible for the effects of Nurr1. Among these potential motifs, site-directed mutational analysis showed that NL1, residing from -35 to -28 bp, was most critical for mediating the transactivation by Nurr1. Strikingly, however, both DNase I footprinting and electrophoretic mobility shift assays showed that NL3, but not NL1 or NL2, has high binding affinity to Nurr1. To determine whether the proximity of these motifs may be important for transactivation by Nurr1 in the transient transfection assay, we generated reporter gene constructs in which NL3 is immediately proximal to the TATA box. Indeed, NL3 was more efficient in this position than NL1 or NL2 for mediating the transactivation by Nurr1. Our results suggest that Nurr1 may play a direct role for specification of DA neurotransmitter identity by activating TH gene transcription in a cell context-dependent manner.
Keywords: cis-acting element; dopaminergic neurons; neurotransmitter phenotype; Nurr1; promoter; transcription; tyrosine hydroxylase
논문정보
- Research article
- 2003년 05월 (BRIC 등록일 2014-04-09)
- 국내+국외 연구진
- 생명과학 > 신경생물학
- 120회 이상 인용된 논문
댓글 작성 로그인
팝업 닫기관련 링크
연구자 키워드
관련분야 연구자보기
소속기관 논문보기
관련분야 논문보기
해당논문 저자보기
