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Involvement of Nurr1 in specifying the neurotransmitter identity of ventral midbrain dopaminergic neurons
Abstract
The mesencephalic dopaminergic (mesDA) system is involved in many brain functions including motor control and motivated behaviour, and is of clinical importance because of its implication in psychiatric disorders and Parkinson's disease. Nurr1, a member of the nuclear hormone receptor superfamily of transcription factors, is essential for establishing the dopaminergic phenotype, because expression of tyrosine hydroxylase (TH), the rate‐limiting enzyme in dopamine synthesis, requires Nurr1. In addition, Nurr1 plays an important role in the maintenance of mesDA neurons. Neonatal Nurr1 knockout mice lack expression of the dopamine transporter (DAT), the vesicular monoamine transporter 2 (VMAT2) and l‐aromatic amino acid decarboxylase (AADC) in addition to TH specifically in mesDA neurons. It is unclear whether the lack of expression of these dopaminergic markers is caused by a maintenance defect or whether the induction of these markers depends on Nurr1 expression. To address this problem, the expression of DAT, VMAT2 and AADC was analysed at embryonic day 12.5 and 14.5. Here we demonstrate that induction of VMAT2 and DAT specifically in mesDA neurons requires Nurr1 expression, whereas AADC expression in mesDA neurons is induced independently of Nurr1 function.
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“RA-containing nanoparticles increased expression of Nurr1 and Pitx3, key regulators of dopaminergic neuronal development and maintenance68,88.”
From Advances and challenges in retinoid delivery systems in regenerative and therapeutic medicine (2020) · cites this paper as [88]
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“Several homodomain transcription factors, including Nurr1 [5], Lmx1b [6],”
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Wever, I., von Oerthel, L., Wagemans, C. M. R. J., & Smidt, M. P. (2019) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2018.00491 · Cited by 14
“In situ hybridization with digoxigenin (DIG)-labeled RNA probes was performed as described (Smits et al., 2003; Smidt et al., 2004).”
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“The orphan nuclear receptor Nurr1 has been shown previously to be critical for the expression of Th, Vmat2 and Dat (Zetterstrom et al., 1997; SaucedoCardenas et al., 1998; Le et al., 1999; Wallen et al., 1999; Smits et al., 2003; Martinat et al., 2006).”
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“And Nurr1deficient animals fail to express TH in midbrain dopaminergic neurons (Saucedo-Cardenas et al., 1998; Smits et al., 2003).”
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“Indeed, Nurr1 KO rats show no expression of DAT and other dopaminergic genes.(51) One explanation to this profile could be linked to different PFC HDAC enzymes concentration, however.”
BackgroundWant of Wnt in Parkinson’s disease: Could sFRP disrupt interplay between Nurr1 and Wnt signaling?
Gamit, N., Dharmarajan, A., Sethi, G., & Warrier, S. R. (2023) · Biochemical Pharmacology · doi:10.1016/j.bcp.2023.115566 · Cited by 13
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Hoekstra, E. J., von Oerthel, L., van der Linden, A. J. A., & Smidt, M. P. (2012) · PLoS ONE · doi:10.1371/journal.pone.0052118 · Cited by 12
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Self-citationWnt1 silencing enhances neurotoxicity induced by paraquat and maneb in SH‑SY5Y cells
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“NURR1 is a transcription factor that regulates the development of DA precursors into mature DA neurons (31).”
Epigenetic Regulation Contributes to Urocortin-Enhanced Midbrain Dopaminergic Neuron Differentiation
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“NR4A2 is also critical for the expression of DA markers such as Th, Slc18a2/Vmat2, and Slc6a3/Dat (Smits et al., 2003).”
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Green, A. L., Eid, A., Zhan, L., Zarbl, H., Guo, G. L., & Richardson, J. (2019) · Frontiers in Genetics · doi:10.3389/fgene.2019.01099 · Cited by 10
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“Exactly by this time, progenitor cells begin to express the transcription factor NURR1 which regulates transcription of the th and dat genes [75, 76].”
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Pallarés, M. E., & Antonelli, M. C. (2014) · Advances in neurobiology · doi:10.1007/978-1-4939-1372-5_3 · Cited by 8
“Nurr1 regulates proteins required for DA synthesis and transport (Zetterstrom et al. 1997; Saucedo-Cardenas et al. 1998; Wallen et al. 1999; Smits et al. 2003; Le et al. 1999; Baffi et al. 1999; Smidt and Burbach 2007; Weidong et al. 2009).”
BackgroundEZH2 Is Essential for Fate Determination in the Mammalian Isthmic Area
Wever, I., Wagemans, C. M. R. J., & Smidt, M. P. (2019) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2019.00076 · Cited by 8
“In situ hybridization with digoxigenin (DIG)-labeled RNA probes was performed as described (Smits et al., 2003; Smidt et al., 2004).”
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“Lmx1a [12], Pitx3 [13], Nurr [14]), it is likely that there are as yet undiscovered factors that modulate the fate of specific midbrain neuronal cell populations during development.”
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“Subsequent studies have revealed that Nurr1 induces essential genes for the mDA neuronal function such as vesicular monoamine transporter 2 (VMAT2), aromatic amino acid carboxylase (AADC), and Ret (GDNF receptor) (Hermanson et al. 2003; Smits et al. 2003; Li et al. 2009).”
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“Transcription factors like EN1/2, Lmx1A/B , and Nurr1 regulate immunological and mitochondrial pathways, making them potential therapeutic targets for PD (Blaudin de Thé et al., 2016; Kim et al., 2003; Saucedo-Cardenas et al., 1998; Smits et al., 2003; Zetterström et al., 1997).”
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“Evidence for the role of orphan nuclear receptor transcription factor NURR1 (nuclear receptor related protein 1) in mesencephalic dopaminergic neuron development came from animal studies demonstrating the lack of TH and cRET (component of GDNF receptor) expression in NURR1 deficient animals [145–148].”
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“In contrast, the Bmp5/7 double mutant, which was investigated at embryonic day (E)10 because these animals do not survive past this age (Solloway and Robertson, 1999), revealed that expression of Nurr1, a transcription factor that is required for the expression of tyrosine hydroxylase (Th), a pivotal marker of the DA…”
BackgroundDopaminergic Differentiation Potential of Neural Precursor Cells Derived from Embryonic Stem Cells
Guerrero-Flores, G., & Covarrubias, L. (2011) · InTech eBooks · doi:10.5772/15392 · Cited by 2
“…such as the presence of tyrosine hydroxylase (the rate-limiting enzyme in dopamine synthesis; TH), vesicular monoamine transporter 2 (Vmat2) and dopamine transporter (DAT) (Zetterstrom et al., 1997, Smits et al., 2003, Saucedo-Cardenas et al., 1998, Kim et al., 2003b, Ferri et al., 2007)(Fig.”
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Funktionelle Analyse des Transkriptionsfaktors Uncx4.1 im murinen Mittelhirn
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Barreto-Valer, K. (2011) · Gredos (University of Salamanca) · doi:10.14201/gredos.115591
Jukkola, T. (2007) · Työväentutkimus Vuosikirja
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“It has been demonstrated that the nuclear transcription factors Nurr1 and Pitx3 control DAT levels during development (Martinat et al., 2006; Smidt et al., 2004; Smits et al., 2003).”
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Metadata
- Authors
- Smits, S. M., Ponnio, T., Conneely, O. M., Burbach, J. P. H., & Smidt, M. P.
- Affiliations
- University Medical Center Utrecht (NL)
- Baylor College of Medicine (US)
- Venue
- European Journal of Neuroscience
- Publisher
- Wiley
- Published
- 2003-10
- Volume
- 18
- Issue
- 7
- Pages
- 1731-1738
- ISSN
- 0953-816X (ISSN-L)
- 1460-9568
- OpenAlex
- W1978387829
- Cited by
- 194
- References
- 47
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 2 · 2023: 4 · 2022: 4 · 2021: 6 · 2020: 11 · 2019: 7 · 2018: 5 · 2017: 11 · 2016: 3 · 2015: 6 · 2014: 7 · 2013: 13 · 2012: 16
- FWCI
- 3.36
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- European Journal of Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nuclear Receptors and Signaling
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Keywords
- Nurr1, midbrain dopaminergic neurons, ventral midbrain, neurotransmitter identity, vesicular monoamine transporter 2, dopamine transporter, tyrosine hydroxylase, transcriptional regulation, embryonic development
- MeSH terms
- Animals, Animals, Newborn, Aromatic-L-Amino-Acid Decarboxylases, DNA-Binding Proteins, Dopamine, Immunohistochemistry, Membrane Glycoproteins, Mesencephalon, Mice, Inbred C57BL, Neurons, Neuropeptides, RNA, Messenger, Transcription Factors, Tyrosine 3-Monooxygenase, In Situ Hybridization, Mice, Knockout, Neurotransmitter Agents, Homeodomain Proteins, Reverse Transcriptase Polymerase Chain Reaction, Membrane Transport Proteins, Vesicular Biogenic Amine Transport Proteins, Vesicular Monoamine Transport Proteins, Mice, Nuclear Receptor Subfamily 4, Group A, Member 2
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