• Molecules and Cells
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• v.43 no.6
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• pp.551-571
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• 2020

Nuclear receptor-related 1 (Nurr1) protein has been identified as an obligatory transcription factor in midbrain dopaminergic neurogenesis, but the global set of human NURR1 target genes remains unexplored. Here, we identified direct gene targets of NURR1 by analyzing genome-wide differential expression of NURR1 together with NURR1 consensus sites in three human neural stem cell (hNSC) lines. Microarray data were validated by quantitative PCR in hNSCs and mouse embryonic brains and through comparison to published human data, including genome-wide association study hits and the BioGPS gene expression atlas. Our analysis identified ~40 NURR1 direct target genes, many of them involved in essential protein modules such as synapse formation, neuronal cell migration during brain development, and cell cycle progression and DNA replication. Specifically, expression of genes related to synapse formation and neuronal cell migration correlated tightly with NURR1 expression, whereas cell cycle progression correlated negatively with it, precisely recapitulating midbrain dopaminergic development. Overall, this systematic examination of NURR1-controlled regulatory networks provides important insights into this protein's biological functions in dopamine-based neurogenesis.

• KSBB Journal
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• v.20 no.5 s.94
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• pp.363-370
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• 2005

Neural stem cells (NSCs) of the central nervous system (CNS) have raised a great interest not only for their importance in basic neural development but also for their therapeutic potentials in neurologically degenerative diseases such as Parkinson's, Alzheimer and stroke. During the CNS development, two molecular cascades determine specification of midbrain dopamine system. In one pathway, FGF-8, sonic hedgehog and transcription factor Nurr1 specify dopamine neurotransmitter phenotype. In the other, transcription factors $Lm{\times}lb\;and\;Pt{\times}3$ are required for induction of dopaminergic neurons. In Nurr1 knockout mouse, tyrosine hydroxylase (TH) positive cells fail to appear in substantia nigra, indicating that Nurr1 is essential in specification of dopaminergic cell phenotype. In this study, we used the immortalized human NSCs retrovirally transduced with Nurr1 gene to probe the Nurr1 mediated mechanism to induce dopamine phenotype. While Nurr1 over-expression alone did not generate dopamine phenotype in NSCs, applications of retinoid and forskolin induced expression of TH and AADC mRNAs. In addition, co-cultures of Nurr1 expressing NSCs with human astrocytes induced a marked increase of TH expression. In this co-culture system, the addition of retinoid and forskolin dramatically increased expression of TH. These results indicate that the immortalized human NSCs with Nurr1 gene could have a clinical utility for cell replacement for the Parkinson patients.

• Asian Pacific Journal of Cancer Prevention
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• v.14 no.3
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• pp.2023-2028
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• 2013

A number of studies have indicated that Nurr1, which belongs to a novel class of orphan nuclear receptors (the NR4A family), is important for carcinogenesis. Here we investigated expression of Nurr1 protein in benign and malignant human prostate tissues and association with clinicopathologic features using immunohistochemical techniques. Moreover, we also investigated the ability of Nurr1 to influence proliferation, migration, invasion and apoptosis of human prostate cancer cells using small interfering RNA silencing. Immunohistochemical analysis revealed that the expression of Nurr1 protein was higher in prostate cancer tissues than in benign prostate tissue (P<0.001), levels being positively correlated with tumor T classification (P = 0.003), N classification (P = 0.017), M classification (P = 0.011) and the Gleason score (P = 0.020) of prostate cancer patients. In vitro, silencing of endogenous Nurr1 attenuated cell proliferation, migration and invasion, and induced apoptosis of prostate cancer cells. These results suggest that Nurr1 may be used as an indicator for prostate cancer progression and be useful for novel potential therapeutic strategies.

• Proceedings of the KSAR Conference
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• 2002.06a
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• pp.85-85
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• 2002

As an effort to direct differentiation of human embryonic stem cells (hES, MB03) to dopamine-producing neuronal cells, we expressed Nurr-l in hES and examined the expression of tyrosine hydroxylase (TH) after bFGF induction. To introduce Nurr-l, hES cells were maintained in humidified chamber with 5% CO₂ and 95% air in DMEM/Fl2 supplemented with FBS (10%), penicillin (100U/㎖), and streptomycin (100㎍/㎖). (omitted)

• Proceedings of the KSAR Conference
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• 2004.06a
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• pp.272-272
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• 2004

The objective of this study is to test whether human embryonic stem cells expressing Nurr1 (Nurr1-transfected hES cells) could be expressed TH according to neuronal differentiation. As an effort to direct differentiation of hES (MB03 registered in NIH) cells to dopamine-producing neuronal cells, Nurr1 was transfected using conventional transfection protocol into MB03 cell and examined the expression of tyrosine hydroxylase (TH) after differentiation induced by retinoic acid (RA) and ascorbic acid (AA). (omitted)

• Proceedings of the Korean Society of Developmental Biology Conference
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• 2003.10a
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• pp.104-104
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• 2003

As an effort to direct differentiation of human embryonic stem (hES, MB03) cells to dopamine-producing neuronal cells, Nurr1 was transfected using conventional transfection protocol into MB03 and examined the expression of tyrosine hydroylase (TH) after differentiation induced by retinoic acid (RA) and ascorbic acid (AA). Experimentally, cells were transfected with linearized Nurr1 cDNA in pcDNA3.1 (+)-hygovernight followed by selection in medium containing hygromycin-B (150 $\mu$/ml). Expression of Nurr1 mRNA was confirmed by RT-PCR and protein by immunocytochemistry in the drug resistant clones. In order to study the effect of Nurr1 protein on the differentiation pattern of ES cells, one of the positive clones (MBNr24) was allowed to form embryoid body (EB) for 2 days and were induced to differentiate for another 4 days using RA (1 $\mu M$) and AA (50 mM) (2-/4+ protocol) followed by selection in N2 medium for 10 or 20 days. After 10 days in N2 medium, cells immunoreactive to anti-GFAP, anti-TH, or anti-NF200 antibodies were 38.8%, 11%, and 20.5%, respectively. After 20 days in N2 medium, cells expressing GFAP, TH, or NF200 were 28%, 15% and 44.8%, respectively but approximately 9% of MB03 expressed TH protein when the cells were induced to differentiate using a similar prorocol, These results suggest that ectopic expression of Nurr1 enhances generation of TH+ cells as well as neuronal cells when hES cells were differentiated by 2-/4+ protocol.

• Proceedings of the KSAR Conference
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• 2004.06a
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• pp.274-274
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• 2004

The purpose of this study is to evaluate the efficacy of in vitro differentiated human embryonic stem (MB03) cells expressing Nurr1 in relief of symptomatic motor behavior of Parkinson's disease (PD) animal models. MB03 cell was genetically modified to express Nurr1 protein (Nr#24/MB03) and was induced to differentiate according to 2- /4+ protocol using retinoic acid and ascorbic acid. (omitted)

• Proceedings of the Korea Environmental Mutagen Society Conference
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• 2003.10a
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• pp.185-185
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• 2003

• Proceedings of the Korean Society of Embryo Transfer Conference
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• 2004.10a
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• pp.98-99
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• 2004

• Proceedings of the Korean Society of Toxicology Conference
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• 2003.10b
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• pp.185-185
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• 2003

In-vitro expanded CNS precursors provide a potentially unlimited source of dopamine (DA) neurons for the experimental treatment in Parkinson's disease. An efficient dopaminergic differentiation from CNS precursors in vitro is limited to mesencephalic precursors isolated from early embryonic ages (embryonic day 11.5 (E11.5)-E12.5).(omitted)