Nurr1 is essential for the induction of the dopaminergic phenotype and the survival of ventral mesencephalic late dopaminergic precursor neurons

Saucedo‐Cárdenas, Odila; Quintana-Hau, Juan D; Le, Weidong; Smidt, Marten P.; Cox, Joke J.; Mayo, Francesco De; Burbach, J. Peter H.; Conneely, Orla M.

doi:10.1073/pnas.95.7.4013

Cited by 666 publications

(559 citation statements)

References 43 publications

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“…Nurr1 gene is of interest since it is a key factor in the neurodevelopmental control of DA neurons in the SNpc and VTA. [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.…”

Section: Discussionmentioning

confidence: 99%

“…Nurr1 has been identified as a critical genetic factor for the terminal differentiation of midbrain DA neurons in the SNpc and VTA. [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.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2007

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The transcription factor Nurr1 (NR4A2) has been found to play a critical role in the development of midbrain dopaminergic neurons. Nurr1 heterozygous ( þ /À) male and female mice expressing 35-40% of normal levels of Nurr1 were generated and examined in animal models related to symptoms of schizophrenia. The Nurr1 ( þ /À) mice displayed hyperactivity in a novel environment, which persisted after administration of the dopamine-mimetic amphetamine and the N-methyl-D-aspartate receptor antagonist phencyclidine. The Nurr1 ( þ /À) mice were deficient in the retention of emotional memory and showed an enhanced response to swim stress. In addition, Nurr1 ( þ /À) male mice displayed a reduced dopamine turnover in the striatum and an enhanced dopamine turnover in the prefrontal cortex, while female mice showed an opposite pattern. These results show that Nurr1 ( þ /À) mice display a pattern of behaviors indicative of potential relevance for symptoms of schizophrenia combined with a gender-specific abnormal dopamine transmission in the striatum and prefrontal cortex, respectively. This suggests that the Nurr1 mutant mouse may be a potential animal model for studies on some of the behavioral and molecular mechanisms underlying schizophrenia.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2007

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“…For example, Nurr1, a member of the Nurr1/Nur77/Nor1 subfamily of receptors, appears to be essential for the migration, differentiation, and survival of dopaminergic neurons of the ventral mesencephon (Zetterstrom et al, 1997;Saucedo-Cardenas et al, 1998;Le et al, 1999;Wallen et al, 1999). Similarly, the orphan nuclear receptor RORα is crucial for maturation and survival of Purkinje cells in the cerebellum (Dussault et al, 1998;Chu and Zingg, 1999;Vogel et al, 2000).…”

Section: Orphan Nuclear Receptors In Cns Developmentmentioning

confidence: 99%

Requirement of the orphan nuclear receptor SF-1 in terminal differentiation of ventromedial hypothalamic neurons

Tran

Lee

Marı́n

et al. 2003

Molecular and Cellular Neuroscience

101

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The ventromedial hypothalamic nucleus (VMN) is known to mediate autonomic responses in feeding and reproductive behaviors. To date, the most definitive molecular marker for the VMN is the orphan nuclear receptor steroidogenic factor-1 (SF-1). However, it is unclear whether SF-1 functions in the VMN as it does in peripheral endocrine organ development where loss of SF-1 results in organ agenesis due to apoptosis. Here, we provide evidence that SF-1 has a distinct role in later stages of VMN development by demonstrating the persistence of VMN precursors, the misexpression of an early marker (NKX2-1) concomitant with the absence of a late marker (BDNF neurotrophin), and the complete loss of projections to the bed nucleus of stria terminalis and the amygdala in sf-1 null mice. Our findings demonstrate that SF-1 is required for terminal differentiation of the VMN and suggest that transcriptional targets of SF-1 mediate normal circuitry between the hypothalamus and limbic structures in the telencephalon.

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“…Interestingly, the five CRs could achieve a significant degree of specificity for TH-expressing cells only in hNPCs and not in the mouse cell culture systems (Romano et al, 2005) Another striking difference in TH gene regulation between the human and mouse TH promoters was observed in a study on NR4A2 (Nurr1), which could not affect in any way human TH gene expression in hNPCs (Jin et al, 2006), in contrast to the mouse and rat systems (Zetterstrom et al, 1997;Castillo et al, 1998;Saucedo-Cardenas et al, 1998;Kim et al, 2002). In addition, a study on the function of three scaffold/matrix attachment regions (S/MARs) present in the promoter at positions (−186/−16) and in the first intron (+645/+755 and +835/+945) of the human TH gene indicated that they might be involved in the differential TH gene regulation among species (Lenartowski and Goc, 2002;Lenartowski et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

Transcription and epigenetic profile of the promoter, first exon and first intron of the human tyrosine hydroxylase gene

Romano

Macaluso

Lucchetti

et al. 2006

Journal Cellular Physiology

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The transcriptional and chromatin profile of the promoter, first exon and first intron of the human TH gene were analyzed in human neuroblastoma BE(2)-C-16 and human renal carcinoma 293FT cell lines. The latter is a cell culture system that is not permissive for TH gene expression, whereas the former has a 50% cell fraction that tests positive for TH. The engineering of a 6.3 kb recombinant human TH promoter revealed the presence of repressors of transcription between positions (−6,244/ −194). The addition of a 1.2 kb fragment of the first intron of the human TH gene (+730/+1,653) enhanced transcriptional activity of the recombinant promoter. However, both constructs were not specific for TH-positive BE(2)-C-16 cells. Chromatin immunoprecipitation (Chip) analysis was carried out on BE(2)-C-16 and 293FT cells to probe sequences of promoter, first exon and first intron of the human TH gene from position (−448/+1,204). The presence of nucleosomes was observed approximately from position (−20/+473) in both cell lines. Chip analysis was then conducted to determine the acetylation of various lysine residues of H3 and H4 in both cell lines. All analyzed lysine residues of H3 and H4 were acetylated in BE(2)-C-16 cells, whereas 293FT cells tested positive for acetylation only in the external lysine residues of the histone tail. Our data are compatible with an active TH gene expression in a 50% cell fraction of BE(2)-C-16 cells. Further analysis of epigenetic programming might lead to the identification of the factors that determine TH gene expression specifically in dopaminergic neurons.The elucidation of the mechanism of human tyrosine hydroxylase (TH) gene regulation is one of the key issues in the field of neurology. The function of TH consists of catalyzing tyrosine hydroxylation in the synthesis of L-dopa (Nagatsu et al., 1964), which is the rate-limiting step in the generation of catecholamine neurotransmitters of the central and peripheral nervous systems (Zigmond et al., 1989). There are a number of important reasons to continue to explore the complex mechanism of TH gene regulation. For instance, aberrant TH gene expression is observed in alcoholism and in psychiatric illnesses, such as schizophrenia and bipolar disorder (Ishiguro et al., 1998). In addition, the degeneration of TH-positive dopaminergic neurons of the substantia nigra is associated with Parkinson's disease (Moore, 2003).Many studies have been conducted to characterize the factors that come into play in TH gene regulation. These studies focused mainly on the human (Kessler et al., 2003;Romano et al., 2005;Jin et al., 2006), mouse (Kim et al., 2003a) and rat models (Gandelman et al., 1990 et al., 2003b). In a previous report, a 13 kb DNA fragment containing the human TH promoter was isolated from a genomic DNA library, sequenced and utilized to generate both a transgenic animal model (Kessler et al., 2003) and a variety of recombinant minimal TH promoters assembled in a self-inactivating lentiviral vector system (Romano et al., 2005). All...

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Nurr1 is essential for the induction of the dopaminergic phenotype and the survival of ventral mesencephalic late dopaminergic precursor neurons

Cited by 666 publications

References 43 publications

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

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

Requirement of the orphan nuclear receptor SF-1 in terminal differentiation of ventromedial hypothalamic neurons

Transcription and epigenetic profile of the promoter, first exon and first intron of the human tyrosine hydroxylase gene

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