Nurr1 enhances transcription of the human dopamine transporter gene through a novel mechanism

Abstract

The importance of the nuclear receptor nurr1 for the appropriate development of mesencephalic dopaminesynthesizing neurons has been clearly demonstrated through the targeted disruption of the nurr1 gene. The persistence of nurr1 expression in adult tissue suggests a possible role for this transcription factor in the maintenance, as well as development, of the dopaminergic phenotype. To address this issue, we analyzed the effects of nurr1 on the transcriptional expression of the human dopamine transporter gene (hDAT), one of the most speci®c phenotypic markers for dopaminergic neurons. Nurr1 enhanced the transcriptional activity of hDAT gene constructs transiently transfected into a newly described cell line (SN4741) that expresses a dopaminergic phenotype, whereas other members of the NGFI-B subfamily of nuclear receptors had lesser or no effects. Nurr1 activation of hDAT was not dependent upon heterodimerization with the retinoid X receptor. Unexpectedly, functional analysis of a series of gene constructs revealed that a region of the hDAT 5 H -¯anking sequence devoid of NGFI-B response element (NBRE)-like sites mediated nurr1 activation. Additional experiments using a nurr1 mutant construct suggest that nurr1 activates hDAT transcription via a novel NBRE-independent mechanism.

Adult mice with reduced Nurr1 expression: an animal model for schizophrenia

“…[16][17][18] Moreover, it regulates genes of importance for the maturation and maintenance of a normal DA phenotype. 16,19,20 In addition, a Nurr1 mutation has been demonstrated in a few schizophrenic patients. 22 Recently, a reduction of Nurr1 expression in the pFCx was found both in schizophrenia and bipolar disorder.…”

“…[16][17][18] Nurr1 has also been shown to regulate key genes of critical importance for DA neurotransmission. 16,19,20 Nurr1 is expressed predominantly in limbic areas and in the ventral midbrain DA neurons, where its distribution overlaps with DA-containing neurons. 21 Since Nurr1 expression continues into adulthood, its role in controlling DA neurons has important implications not only for the developing brain, but also for the adult brain.…”

Nur77 Gene Knockout Alters Dopamine Neuron Biochemical Activity and Dopamine Turnover

“…Since the DAT represents a putative target of Nur-dependent transcriptional activity (Hermanson et al 2003;Sacchetti et al 2001), we also compared DAT binding capacity in Nur77 +/+ and −/− mice. The density of DAT binding sites was evaluated in the SNpc, VTA, and striatal sections.…”

“…Nurr1 can activate the transcription of DA biosynthetic enzymes, such as TH and L-aromatic amino-acid decarboxylase (AADC) in cultured cell lines (Hermanson et al 2003;Iwawaki et al 2000;Sakurada et al 1999). In addition, Nurr1 can modulate the expression of the DA transporter (DAT) and vesicular monoamine transporter (VMAT) (Hermanson et al 2003;Sacchetti et al 2001). Responsive elements sensitive to Nurr1 present in those gene promoters can also represent putative targets for other Nur members (Maira et al 1999;Perlmann and Jansson 1995).…”

Association and linkage of allelic variants of the dopamine transporter gene in ADHD

“…DAT1 5 0 untranslated (UTR) and flanking regions show a low evolutionary structural similarity between mouse and human (http://genome.ucsc.edu). The DAT1 5 0 flanking region is characterized by the lack of TATA and CAAT boxes, a high GC content, TATA-like sequences and binding sites for transcription factors (i.e., Sp1, Sp3, Nurr1 [20][21][22] ). Common haplotypes in the DAT1 5 0 flanking region were described by different groups.…”