The NR4A nuclear receptor family in eosinophils.
Hashida R, Ohkura N, Saito H, Tsujimoto G
This review discusses how NR4A receptors influence eosinophil survival in allergic diseases like atopic dermatitis, rather than addressing the neurological aspects of NR4A2 syndrome. It suggests that drugs could potentially treat allergies by triggering eosinophil death through these receptors.
- NR4A family includes Nur77, Nurr1, and NOR1 orphan nuclear receptors.
- Nur77 and NOR1 modulate leukocyte functions in immune diseases.
- CD30 stimulation increases Nur77 and NOR1 expression in eosinophils.
- High NR4A levels promote eosinophil apoptosis in atopic dermatitis.
- Low molecular weight compounds may treat allergies via NR4A pathways.
Carnosol, a component of rosemary (Rosmarinus officinalis L.) protects nigral dopaminergic neuronal cells.
Kim SJ, Kim JS, Cho HS, Lee HJ, Kim SY, Kim S, Lee SY, Chun HS
Carnosol, a compound found in rosemary, protects dopaminergic neurons from toxin-induced damage in cell cultures by reducing cell death and boosting key neuronal markers. This preclinical finding suggests potential for future Parkinson's disease treatments but does not provide evidence of benefit for humans or NR4A2-related syndromes.
- Carnosol improves survival of dopaminergic neurons exposed to rotenone toxin in lab dishes.
- The compound reduces caspase-3, a marker of cell death, in these cultured cells.
- Carnosol increases levels of tyrosine hydroxylase and Nurr1, proteins vital for dopamine function.
- This is an in vitro study with no human or animal data presented.
NR4A2 genetic variation in sporadic Parkinson's disease: a genewide approach.
Healy DG, Abou-Sleiman PM, Ahmadi KR, Gandhi S, Muqit MM, Bhatia KP, Quinn NP, Lees AJ, Holton JL, Revesz T, Wood NW
Common genetic variations in the NR4A2 gene do not affect the risk of sporadic Parkinson's disease in Caucasians, according to a large study of patients and controls.
- NR4A2 variations do not influence sporadic PD risk in Caucasians
- Study analyzed 802 patients and 784 controls
- No significant link found between NR4A2 haplotypes and PD
- Findings challenge NR4A2's role as a susceptibility factor
Chronic cocaine administration modulates the expression of transcription factors involved in midbrain dopaminergic neuron function.
Leo D, di Porzio U, Racagni G, Riva MA, Fumagalli F, Perrone-Capano C
Chronic cocaine exposure in rats reduces the levels of Nurr1 and Pitx3, two transcription factors critical for dopaminergic neuron function, with effects lasting weeks after drug cessation. This study demonstrates that environmental toxins can downregulate these specific genes, but it does not provide evidence for treating NR4A2-related syndromes.
- Chronic cocaine lowers Nurr1 and Pitx3 transcripts in rat midbrain.
- Effects persist two weeks after stopping drug administration.
- Study uses rats, not humans or genetic models of NR4A2 syndrome.
- Focuses on drug-induced changes, not inherited mutations.
Comparative analysis of layer-specific genes in Mammalian neocortex.
Watakabe A, Ichinohe N, Ohsawa S, Hashikawa T, Komatsu Y, Rockland KS, Yamamori T
This study maps the location and connections of specific neuron groups in monkey and mouse brains using gene expression markers. It identifies distinct subpopulations of deep-layer cortical neurons that express Nurr1 (NR4A2) and describes their projection patterns.
- Nurr1-expressing neurons reside in layer 6 of the primate neocortex.
- These neurons send corticocortical projections but not corticopulvinar projections.
- Gene expression profiles differ between monkeys and mice in cortical layers.
- The research focuses on basic brain architecture, not disease mechanisms.
Regulation of osteoblast differentiation by Nurr1 in MC3T3-E1 cell line and mouse calvarial osteoblasts.
Lee MK, Choi H, Gil M, Nikodem VM
Nurr1 promotes the differentiation of bone-forming cells, as reducing its levels in cell cultures and mouse models decreases key markers of bone development. This study establishes a role for Nurr1 in skeletal biology but does not address neurological symptoms or treatments relevant to NR4A2-related syndromes.
- Nurr1 supports osteoblast differentiation in bone cells.
- Reducing Nurr1 lowers expression of bone marker genes.
- Overexpressing Nurr1 increases bone marker gene expression.
- The study uses cell lines and mouse models only.
- No findings relate to neurological or developmental outcomes.
Microarray analyses support a role for Nurr1 in resistance to oxidative stress and neuronal differentiation in neural stem cells.
Sousa KM, Mira H, Hall AC, Jansson-Sjöstrand L, Kusakabe M, Arenas E
Nurr1 promotes the survival and differentiation of dopaminergic neurons by enhancing resistance to oxidative stress and regulating specific growth factors. The study identifies tenascin-C as a key molecule that Nurr1 controls to manage the timing of neuronal maturation.
- Nurr1 expression increases neural stem cell resistance to oxidative stress.
- Nurr1 reduces markers of cell death in developing neurons.
- Conditioned medium from Nurr1-expressing cells boosts dopaminergic neuron survival.
- Nurr1 regulates tenascin-C, which delays the maturation of dopaminergic neurons.
The zebrafish mutation m865 affects formation of dopaminergic neurons and neuronal survival, and maps to a genetic interval containing the sepiapterin reductase locus.
Ettl AK, Holzschuh J, Driever W
This study identifies a zebrafish mutation that disrupts the development and survival of dopaminergic neurons and other neural cell types. The genetic defect maps to the sepiapterin reductase locus, suggesting this enzyme is critical for neuronal maintenance rather than NR4A2 function itself.
- The mutation causes defects in dopaminergic neuron development and survival in zebrafish embryos.
- Other neurotransmitter systems, including serotonergic and cholinergic pathways, are also impaired.
- Increased cell death occurs in the retina and optic tectum starting at 24 hours post-fertilization.
- The genetic defect maps to sepiapterin reductase, not NR4A2/NURR1.
- NURR1 expression is reduced only in the retina, indicating secondary effects.
Multiple signaling pathways regulate the transcriptional activity of the orphan nuclear receptor NURR1.
Sacchetti P, Carpentier R, Ségard P, Olivé-Cren C, Lefebvre P
This study identifies specific signaling proteins that directly control the activity of the NR4A2 transcription factor in developing dopamine neurons. It shows that ERK2 and ERK5 increase NR4A2 function while LIM Kinase 1 decreases it, establishing a molecular mechanism for how these pathways influence neuron development.
- ERK2 and ERK5 kinases enhance NR4A2 transcriptional activity in mesencephalic cells.
- LIM Kinase 1 inhibits NR4A2 transcriptional activity.
- NR4A2 recruits ERK5 to specific promoters, acting as a convergence point for signaling pathways.
- The study uses cell lines and does not involve human patients or animal models.
Characterization of the Nurr1 ligand-binding domain co-activator interaction surface.
Volakakis N, Malewicz M, Kadkhodai B, Perlmann T, Benoit G
This study maps a specific surface on the Nurr1 protein that is essential for its function and links this activity to how quickly the protein breaks down in cells. It identifies a unique interaction site distinct from standard nuclear receptor mechanisms, providing structural details about how NR4A2 operates at the molecular level.
- Nurr1 lacks a traditional ligand-binding cavity but uses an alternative surface for co-activator interaction.
- Mutations in this hydrophobic region generally reduce or abolish Nurr1 transcriptional activity.
- One specific mutation (K577) drastically increases Nurr1 activity, highlighting the region's regulatory role.
- Nurr1 activity correlates with its rate of proteasome-dependent degradation within the cell.
- The findings define a unique co-activator binding mechanism specific to the NR4A family of receptors.
VIP is a transcriptional target of Nurr1 in dopaminergic cells.
Luo Y, Henricksen LA, Giuliano RE, Prifti L, Callahan LM, Federoff HJ
The Nurr1 protein directly controls the production of VIP, a molecule that helps dopaminergic neurons survive stress. This mechanism explains how Nurr1 supports neuron health but does not provide immediate treatment options for NR4A2-related syndromes.
- Nurr1 activates the gene for vasoactive intestinal peptide (VIP).
- VIP protects dopaminergic neurons from oxidative stress damage.
- This study uses cell lines and mouse models only.
- No human clinical data or treatment trials are reported.
The K+ channel gene, Kcnb1: genomic structure and characterization of its 5'-regulatory region as part of an overlapping gene group.
Roder K, Koren G
This study maps the genetic structure of the Kcnb1 potassium channel gene and identifies a specific binding site for Nurr1 (NR4A2) that regulates its expression in heart and brain tissue. Mutating this Nurr1 binding site significantly reduces the activity of the gene's promoter, confirming a direct regulatory link between NR4A2 and Kcnb1 transcription.
- Kcnb1 has two promoters active in brain and heart tissue.
- Nurr1 binds directly to a specific site on the Kcnb1 promoter.
- Disrupting this Nurr1 binding site lowers gene expression significantly.
- The study focuses on molecular mechanisms, not clinical outcomes or treatments.
[Effects of Nurr1 down-regulation on the expression of tyrosine hydroxylase and neurite extension in dopaminergic cells.].
Wu YC, Cai YQ, Zhao YB, Fei J
Silencing the Nurr1 gene in dopaminergic cells reduces tyrosine hydroxylase levels and impairs neurite extension. This confirms that Nurr1 is essential for maintaining the functional phenotype of these neurons in vitro.
- Nurr1 knockdown significantly lowers tyrosine hydroxylase mRNA and protein.
- Reduced Nurr1 expression inhibits neurite extension in dopaminergic cells.
- The study uses a mouse dopaminergic cell line (MN9D).
- No human data or clinical treatment implications are presented.
NR4A orphan nuclear receptors are transcriptional regulators of hepatic glucose metabolism.
Pei L, Waki H, Vaitheesvaran B, Wilpitz DC, Kurland IJ, Tontonoz P
This study identifies NR4A orphan nuclear receptors, including Nurr1 (NR4A2), as key regulators of liver glucose production rather than brain function. It demonstrates that these receptors control gluconeogenesis and blood sugar levels in the context of diabetes and fasting.
- NR4A receptors regulate hepatic glucose metabolism, not dopaminergic neuron survival.
- Nurr1 expression increases during fasting and in diabetic mouse models.
- Activating Nurr1 raises blood glucose levels in vivo.
- Inhibiting Nurr1 lowers blood glucose in diabetic mice.
- The findings focus on metabolic disease mechanisms, not neurodevelopment.
Nur77 gene knockout alters dopamine neuron biochemical activity and dopamine turnover.
Gilbert F, Morissette M, St-Hilaire M, Paquet B, Rouillard C, Di Paolo T, Lévesque D
This study shows that removing the Nur77 gene in mice disrupts dopamine regulation, leading to increased movement and altered chemical processing of dopamine. These findings confirm that Nur77 plays a role in controlling dopamine neuron activity but do not provide direct evidence for human treatment strategies.
- Nur77 knockout mice show higher spontaneous locomotor activity than normal mice.
- Dopamine turnover is disturbed, with elevated levels of the metabolite DOPAC.
- The study uses mouse models, not human patients or clinical data.
- Results link Nur77 to dopamine biochemistry but offer no therapeutic guidance.
Enriched NCAM-positive cells form functional dopaminergic neurons in the rat model of Parkinson's disease.
Ravindran G, Rao HS
Researchers develop a method to generate functional dopaminergic neurons from human stem cells that do not form tumors when transplanted into Parkinson's disease rat models. This approach uses magnetic sorting to enrich for specific neuroprogenitor cells, ensuring safe differentiation into dopamine-producing neurons. The study provides preclinical proof-of-concept for cell replacement therapies in Parkinson's disease.
- Human stem cells differentiate into functional dopaminergic neurons without tumor formation in rats.
- Magnetic sorting enriches neuroprogenitor cells, preventing teratoma risk during transplantation.
- Transplanted cells integrate and express key dopamine markers like TH and DAT.
- Study focuses on Parkinson's disease cell therapy, not NR4A2 genetics or treatment.
Nuclear receptors Nur77, Nurr1, and NOR-1 expressed in atherosclerotic lesion macrophages reduce lipid loading and inflammatory responses.
Bonta PI, van Tiel CM, Vos M, Pols TW, van Thienen JV, Ferreira V, Arkenbout EK, Seppen J, Spek CA, van der Poll T, Pannekoek H, de Vries CJ
This study shows that NR4A2 and related proteins reduce inflammation and lipid buildup in human immune cells found in artery plaques. The findings do not provide information about the neurological or developmental symptoms associated with NR4A2 syndrome in children.
- NR4A2 is expressed in macrophages within human atherosclerotic lesions.
- Overexpression of NR4A2 reduces inflammatory cytokine production in these cells.
- NR4A2 activity decreases lipid uptake and foam cell formation in macrophages.
- The research focuses on vascular disease, not neurodevelopment or Parkinson's.
Embryonic stem cell-derived neuron models of Parkinson's disease exhibit delayed neuronal death.
Yamashita H, Nakamura T, Takahashi T, Nagano Y, Hiji M, Hirabayashi T, Amano T, Yagi T, Sakai N, Kohriyama T, Matsumoto M
This study uses mouse embryonic stem cells to create a model of Parkinson's disease that mimics the slow, delayed death of dopaminergic neurons seen in patients. The model demonstrates how mutant alpha-synuclein proteins cause oxidative stress and eventual cell death over several weeks. This provides a new tool for studying the underlying mechanisms of neurodegeneration rather than offering direct insights into NR4A2-related syndromes.
- Researchers created dopaminergic neurons from mouse stem cells expressing mutant alpha-synuclein.
- These neurons showed increased susceptibility to oxidative and mitochondrial stress.
- Cell death occurred gradually over one month, mimicking delayed neurodegeneration.
- The model did not show cell death in oligodendrocytes, indicating specificity.
- This serves as a prototype for studying Parkinson's pathophysiology.
PGC-1alpha is induced by parathyroid hormone and coactivates Nurr1-mediated promoter activity in osteoblasts.
Nervina JM, Magyar CE, Pirih FQ, Tetradis S
This study shows that parathyroid hormone triggers a molecular pathway in bone cells where Nurr1 works with PGC-1alpha to activate gene expression. The findings are limited to mouse osteoblasts and do not address the neurological or developmental aspects of NR4A2-related syndromes.
- Nurr1 interacts directly with PGC-1alpha in bone cells.
- Parathyroid hormone induces both Nurr1 and PGC-1alpha via cAMP signaling.
- This interaction increases the activity of bone-specific genes like osteocalcin.
- The research focuses exclusively on mouse osteoblasts, not neurons.
- No clinical data or human patient outcomes are reported.
Neuroprotective effects of cystamine in aged parkinsonian mice.
Tremblay ME, Saint-Pierre M, Bourhis E, Lévesque D, Rouillard C, Cicchetti F
Cystamine protects dopaminergic neurons in aged mice with Parkinson-like symptoms by preserving Nurr1 levels and dopamine-related markers. This preclinical study demonstrates neuroprotective effects in an animal model but does not provide evidence for human treatment or NR4A2-specific therapy.
- Cystamine preserves dopaminergic neurons in aged mice exposed to Parkinson-inducing toxins.
- Treatment increases Nurr1 mRNA and dopamine transporter expression in the substantia nigra.
- The study uses an animal model, not human patients or NR4A2 genetic variants.
- No clinical data exists for cystamine efficacy in humans with NR4A2-related syndromes.
Differential actions of the proneural genes encoding Mash1 and neurogenins in Nurr1-induced dopamine neuron differentiation.
Park CH, Kang JS, Kim JS, Chung S, Koh JY, Yoon EH, Jo AY, Chang MY, Koh HC, Hwang S, Suh-Kim H, Lee YS, Kim KS, Lee SH
The gene Mash1 helps Nurr1 drive the maturation of dopamine neurons, while related genes like Neurogenins block this process. This suggests that balancing these opposing genetic signals is critical for proper dopamine neuron development.
- Mash1 promotes full maturation of dopamine neurons induced by Nurr1.
- Neurogenins and NeuroD repress Nurr1-driven dopamine neuron markers.
- The helix-loop-helix domain determines whether these factors activate or inhibit.
- This study uses cell culture models, not human patients or animals.
Stable expression of a neuronal dopaminergic progenitor phenotype in cell lines derived from human amniotic fluid cells.
McLaughlin D, Tsirimonaki E, Vallianatos G, Sakellaridis N, Chatzistamatiou T, Stavropoulos-Gioka C, Tsezou A, Messinis I, Mangoura D
Human amniotic fluid cells can be cultured to form stable cell lines that express markers of midbrain dopaminergic neurons. These cells retain this specific neuronal phenotype through many generations in the lab.
- Amniotic fluid cells form homogeneous cell lines lacking HLAII antigenicity.
- Cells strongly express NURR1, EN-1, and c-RET, essential for dopaminergic neuron survival.
- Cells produce dopamine synthesis enzymes like TH and VMAT2.
- The dopaminergic phenotype remains stable up to passage 36.
- This model resembles neurons derived from embryonic stem cells.
Early postnatal isolation reduces dopamine levels, elevates dopamine turnover and specifically disrupts prepulse inhibition in Nurr1-null heterozygous mice.
Eells JB, Misler JA, Nikodem VM
Reduced Nurr1 levels combined with social isolation disrupt dopamine signaling and sensorimotor gating in mice, modeling how genetic risk interacts with environmental factors. This study highlights that dopaminergic deficits in NR4A2-related conditions may be exacerbated by early-life environmental stressors.
- Nurr1 heterozygous mice show disrupted prepulse inhibition only when raised in isolation.
- Isolation reduces dopamine levels and increases turnover in key brain regions.
- Genetic predisposition and environment interact to alter dopamine neurotransmission.
- Wild-type mice are unaffected by isolation regarding sensorimotor gating.
Reduction of dopamine-related transcription factors Nurr1 and NGFI-B in the prefrontal cortex in schizophrenia and bipolar disorders.
Xing G, Zhang L, Russell S, Post R
This study finds that levels of the transcription factors Nurr1 (NR4A2) and NGFI-B are significantly reduced in the prefrontal cortex of people with schizophrenia and bipolar disorder. These findings link lower NR4A2 expression to psychiatric conditions rather than providing direct evidence for NR4A2-related syndrome or its treatment.
- Nurr1 and NGFI-B levels are lower in the brains of patients with schizophrenia and bipolar disorder.
- The study measures mRNA and protein in post-mortem brain tissue, not living patients.
- Results do not establish a causal link between NR4A2 levels and specific symptoms.
- This research focuses on psychiatric disorders, not developmental syndromes caused by NR4A2 mutations.
Gene regulation by hypoxia and the neurodevelopmental origin of schizophrenia.
Schmidt-Kastner R, van Os J, W M Steinbusch H, Schmitz C
This review identifies NR4A2 as a gene potentially linked to schizophrenia that is regulated by low oxygen levels during brain development. It suggests that environmental factors like hypoxia may interact with this genetic susceptibility to influence neurodevelopmental outcomes.
- NR4A2 is listed among genes associated with schizophrenia susceptibility.
- The paper links NR4A2 regulation to embryonic and fetal brain hypoxia.
- It proposes that vascular function and oxygen levels affect gene expression.
- No clinical data or treatment implications for NR4A2 syndrome are provided.
Neuropilin1 is a direct downstream target of Nurr1 in the developing brain stem.
Hermanson E, Borgius L, Bergsland M, Joodmardi E, Perlmann T
This study identifies Neuropilin-1 as a direct genetic target of Nurr1 in the developing brain stem, linking the protein to axon guidance and angiogenesis processes. It confirms this relationship through cell line experiments and observations in mice lacking Nurr1.
- Nurr1 directly regulates Neuropilin-1 gene expression in the brain stem.
- Neuropilin-1 supports axon guidance and blood vessel formation.
- Evidence comes from cell lines and Nurr1-deficient mice, not humans.
Induction dopamine releasing cells from mouse embryonic stem cells and their long-term culture.
Moriyasu K, Yamazoe H, Iwata H
Researchers successfully generated dopamine-releasing cells from mouse embryonic stem cells and maintained their function for nearly two months. Encapsulating these cell aggregates in a protective hydrogel preserved their ability to release dopamine without harming the cells.
- Dopaminergic neurons derived from mouse stem cells released dopamine for 58 days in culture.
- Agarose microencapsulation protected cells and slightly enhanced dopamine release compared to unencapsulated groups.
- The study focuses on manufacturing techniques for cell therapy, not human genetics or clinical outcomes.
- No evidence is provided regarding NR4A2 variants, human patients, or current treatment efficacy.
12-O-tetradecanoyl-phorbol-13-acetate-dependent up-regulation of dopaminergic gene expression requires Ras and neurofibromin in human IMR-32 neuroblastoma.
Mangoura D, Theofilopoulos S, Karouzaki S, Tsirimonaki E
This study shows that specific signaling pathways involving Ras and neurofibromin can increase dopamine-related gene expression in human neuroblastoma cells, independent of the NR4A2 protein. The findings suggest a complex regulatory hierarchy where neurofibromin levels may influence NR4A2 expression, but the primary mechanism described does not directly involve NR4A2 activation.
- Dopamine gene upregulation occurs via Ras and neurofibromin pathways in human cells.
- This effect is independent of NR4A2 (Nurr1) transcription factor activity.
- Neurofibromin manipulation alters NR4A2 message levels, suggesting developmental hierarchy.
- Cell hypertrophy and secretory activity increase alongside dopamine gene expression.
Tyrosine hydroxylase gene regulation in human neuronal progenitor cells does not depend on Nurr1 as in the murine and rat systems.
Jin H, Romano G, Marshall C, Donaldson AE, Suon S, Iacovitti L
This study shows that the human tyrosine hydroxylase gene does not rely on Nurr1 for regulation, unlike in mice. Silencing Nurr1 in human cells has no effect on tyrosine hydroxylase expression, indicating that mouse models do not accurately reflect this specific genetic mechanism in humans.
- Nurr1 is required for tyrosine hydroxylase regulation in rodents but not in humans.
- Human tyrosine hydroxylase promoter lacks functional binding sites for Nurr1.
- Silencing Nurr1 does not alter tyrosine hydroxylase expression in human neuronal cells.
- Mouse models may provide misleading data regarding this specific gene interaction.
Adult rat bone marrow stromal cells express genes associated with dopamine neurons.
Kramer BC, Woodbury D, Black IB
Adult rat bone marrow stromal cells naturally express Nurr-1 and other genes essential for dopamine neuron development, suggesting they could serve as a source for cell replacement therapies in Parkinson's disease. Treatment with Sonic Hedgehog signaling molecules increases cell growth, indicating these cells possess functional receptors relevant to neuronal survival.
- Rat bone marrow cells express Nurr-1, critical for dopamine neuron development.
- These cells also transcribe genes involved in midbrain formation and dopamine survival.
- Sonic Hedgehog signaling promotes DNA synthesis in these cultured cells.
- Findings suggest potential utility for Parkinson's disease cell therapy strategies.