Enforcement of γδ-lineage commitment by the pre-T-cell receptor in precursors with weak γδ-TCR signals.
Zarin P, Wong GW, Mohtashami M, Wiest DL, Zúñiga-Pflücker JC
This study shows that weak signals from the γδ T-cell receptor can lead to incomplete development of γδ T cells, but a second signal from the pre-T-cell receptor helps enforce the γδ lineage choice, ensuring proper maturation and function. The gene Nr4a2 is upregulated when this reinforcing signal is present, linking it to lineage commitment.
- Weak γδ-TCR signals fail to fully drive γδ T-cell development
- Pre-TCR signals reinforce γδ lineage choice when γδ-TCR signals are weak
- Nr4a2 is upregulated during enforced γδ-lineage commitment
- Functional γδ T cells require both strong γδ-TCR and pre-TCR signals
- Cumulative signal strength determines T-cell lineage fate
Inhibition of Methicillin-resistant Staphylococcus aureus-induced cytokines mRNA production in human bone marrow derived mesenchymal stem cells by 1,25-dihydroxyvitamin D3.
Maiti A, Jiranek WA
This study shows that Vitamin D3 reduces inflammation in human bone marrow stem cells infected with MRSA by suppressing the NR4A2 gene and related inflammatory signals. The research demonstrates a molecular mechanism where Vitamin D3 interacts with NR4A2 to silence pro-inflammatory genes, but it does not test treatments for NR4A2-related neurodevelopmental syndromes.
- NR4A2 expression increases in human stem cells during MRSA bone infection.
- Vitamin D3 suppresses NR4A2 and inflammatory cytokines in these cells.
- The study focuses on immune response, not neurological development or function.
- No clinical data or relevance to NR4A2 syndrome symptoms is provided.
Regulation of NR4A by nutritional status, gender, postnatal development and hormonal deficiency.
Pérez-Sieira S, López M, Nogueiras R, Tovar S
This study shows that NR4A gene expression in fat tissue changes based on fasting, gender, and hormonal status. It does not provide information about NR4A2-related syndrome, clinical outcomes, or treatments for children.
- NR4A genes regulate energy balance and glucose metabolism in white adipose tissue.
- Fasting increases expression of all three NR4A isoforms independently of leptin.
- Sex steroid hormones modulate NR4A expression differently in males and females.
Retraction for Kitagawa et al., A regulatory circuit mediating convergence between Nurr1 transcriptional regulation and Wnt signaling.
Kitagawa H, Ray WJ, Glantschnig H, Nantermet PV, Yu Y, Leu CT, Harada SI, Kato S, Freedman LP
This paper is retracted and no longer valid scientific evidence. It previously investigated the interaction between Nurr1 (NR4A2) and Wnt signaling pathways in a preclinical context.
- The publication has been officially retracted by the journal.
- No findings from this study should be considered reliable or applicable.
- It was a molecular biology study, not a clinical trial.
Induction of neurotrophic and differentiation factors in neural stem cells by valproic acid.
Almutawaa W, Kang NH, Pan Y, Niles LP
Valproic acid increases the expression of key neurotrophic factors and Nurr1 in neural stem cells through an epigenetic mechanism. This suggests the drug may support the development or protection of dopamine-related neurons.
- Valproic acid boosts CDNF and GDNF protein levels in neural stem cells.
- The drug significantly increases mRNA for Nurr1, a critical transcription factor.
- Effects occur via histone hyperacetylation, indicating an epigenetic mechanism.
- Study uses C17.2 neural stem cell lines, not human patients or animals.
The long-term effects of the herbicide atrazine on the dopaminergic system following exposure during pubertal development.
Li Y, Sun Y, Yang J, Wu Y, Yu J, Li B
Exposure to the herbicide atrazine during puberty in rats causes lasting damage to the brain's dopamine system, including reduced dopamine levels and lower levels of a key protective protein called Nurr1, even in adulthood. This suggests early-life exposure to environmental toxins may have long-term neurological consequences.
- Atrazine exposure during puberty harms dopamine systems in rats
- Dopamine levels remain low in adult rats
- Nurr1, a protective brain protein, is reduced
- Early-life exposure leads to lasting brain changes
- Environmental toxins may affect neurodevelopment
Stress and glucocorticoid regulation of NR4A genes in mice.
Helbling JC, Minni AM, Pallet V, Moisan MP
Stress increases NR4A gene activity in mouse brain and adrenal regions, but this effect is minimal in higher cerebral areas like the hippocampus. Glucocorticoid signaling influences these genes in stress-response centers but not in the cortex or hippocampus.
- Stress markedly induces NR4A mRNA in mouse adrenals and pituitary.
- Induction in the hypothalamus is significant but moderate compared to peripheral tissues.
- Higher brain regions like the cortex and hippocampus show little to no stress-induced change.
- Glucocorticoid signaling affects Nur77 expression in the hypothalamus and pituitary only.
- The study uses mouse models, not human patients or clinical data.
Exposure to atrazine during gestation and lactation periods: toxicity effects on dopaminergic neurons in offspring by downregulation of Nurr1 and VMAT2.
Sun Y, Li YS, Yang JW, Yu J, Wu YP, Li BX
Exposure to the herbicide atrazine during pregnancy and lactation reduces dopamine levels and downregulates Nurr1 and VMAT2 in the brains of rat offspring. This study demonstrates that environmental toxins can disrupt dopaminergic development through mechanisms involving NR4A2 (Nurr1), providing a potential environmental risk factor for neurodevelopmental issues. The findings are limited to animal models and do not establish direct clinical relevance for human patients with NR4A2-related syndromes.
- Atrazine exposure during gestation and lactation lowers dopamine in rat offspring brains.
- The herbicide downregulates Nurr1 (NR4A2) and VMAT2 mRNA expression in the ventral midbrain.
- Reduced Nurr1 correlates with decreased dopamine transporter activity and storage capacity.
- Effects persist into adulthood, suggesting long-term neurodevelopmental impact from early exposure.
Induction of dopaminergic neurons from human Wharton's jelly mesenchymal stem cell by forskolin.
Paldino E, Cenciarelli C, Giampaolo A, Milazzo L, Pescatori M, Hassan HJ, Casalbore P
Researchers successfully converted human umbilical cord stem cells into dopaminergic neurons using forskolin, a compound that increases cellular cAMP levels. The study confirms this method upregulates key dopaminergic markers including Nurr1 (NR4A2), NeuroD1, and tyrosine hydroxylase in vitro.
- Forskolin induces dopaminergic neuron differentiation from human Wharton's jelly stem cells.
- The process significantly upregulates Nurr1, NeuroD1, and TH protein expression.
- Microarray analysis shows modulation of over 1,500 neuronal signaling genes.
- Treatment increases neurotrophin Trk receptors and brain-derived neurotrophic factor release.
Nur77 suppresses pulmonary artery smooth muscle cell proliferation through inhibition of the STAT3/Pim-1/NFAT pathway.
Liu Y, Zhang J, Yi B, Chen M, Qi J, Yin Y, Lu X, Jasmin JF, Sun J
This study shows that Nur77 inhibits the growth of lung artery cells by blocking a specific signaling pathway, suggesting it could be a target for treating pulmonary hypertension. The research is conducted entirely in rat models and cell cultures without any human data or direct link to NR4A2-related neurological syndromes.
- Nur77 suppresses lung artery smooth muscle cell proliferation in rats.
- It works by inhibiting the STAT3/Pim-1/NFAT signaling pathway.
- The study focuses on pulmonary hypertension, not neurological development.
- No human participants or NR4A2 genetic variants were analyzed.
Foxa2 acts as a co-activator potentiating expression of the Nurr1-induced DA phenotype via epigenetic regulation.
Yi SH, He XB, Rhee YH, Park CH, Takizawa T, Nakashima K, Lee SH
The transcription factor Foxa2 helps activate dopamine-producing neuron genes by preventing Nurr1 from being blocked by repressor proteins. This interaction opens up the DNA structure, allowing essential dopamine-related genes to turn on during brain development.
- Foxa2 competes with repressor proteins to free Nurr1 for gene activation.
- This mechanism increases histone acetylation, opening chromatin at dopamine gene promoters.
- The study uses mouse midbrain neuron models to map developmental pathways.
- No human data or clinical treatment implications are presented.
Angiotensin II receptor blockers differentially affect CYP11B2 expression in human adrenal H295R cells.
Matsuda K, Uruno A, Kogure N, Sugawara K, Shimada H, Nezu M, Saito-Ito T, Iki Y, Kudo M, Shimizu K, Sato I, Yoshikawa T, Satoh F, Ito R, Yokoyama A, Rainey WE, Saito-Hakoda A, Ito S, Sugawara A
This study investigates how blood pressure medications affect aldosterone production in human adrenal cells, finding that one specific drug, telmisartan, unexpectedly increases the expression of NURR1 and aldosterone. The research focuses on molecular mechanisms within cell lines rather than clinical outcomes or NR4A2-related neurological syndromes. It provides no direct evidence for treatment strategies or phenotypic understanding relevant to NR4A2 syndrome.
- Telmisartan increases NURR1 and aldosterone production in human adrenal cells via a specific genetic pathway.
- Other ARBs suppress aldosterone transcription, showing drug-specific effects on this pathway.
- The study uses cell lines to map molecular interactions, not patient data or animal models.
- Findings relate to blood pressure regulation, not the dopaminergic or neurological aspects of NR4A2 syndrome.
Functional roles of Nurr1, Pitx3, and Lmx1a in neurogenesis and phenotype specification of dopamine neurons during in vitro differentiation of embryonic stem cells.
Hong S, Chung S, Leung K, Hwang I, Moon J, Kim KS
This study uses embryonic stem cells to show how Nurr1, Pitx3, and Lmx1a work together to create dopamine neurons. It finds that these proteins directly activate key genes but also have distinct roles in cell type specification.
- Overexpressing Nurr1, Pitx3, or Lmx1a boosts dopamine neuron development from stem cells.
- Nurr1 directly activates the tyrosine hydroxylase gene promoter.
- Pitx3 and Lmx1a drive neurogenesis by activating the Ngn2 gene.
- Nurr1 uniquely produces non-neuronal TH-positive cells in this system.
- The factors have both overlapping and distinct functions in cell fate.
Nur transcription factors in stress and addiction.
Campos-Melo D, Galleguillos D, Sánchez N, Gysling K, Andrés ME
This review explains how NR4A2 and related proteins help the brain adapt to stress and addiction by changing gene expression in reward circuits. It does not provide new information about NR4A2-related syndrome, treatment options, or clinical outcomes for affected children.
- NR4A2 is part of a family of transcription factors induced by stress and drugs of abuse.
- These proteins regulate gene expression in the brain's motivation and reward circuits.
- The paper reviews mechanisms linking NR4A2 to chronic stress and addiction biology.
- No clinical data, patient phenotypes, or therapeutic strategies for NR4A2 syndrome are presented.
Twenty-Four Genes are Upregulated in Patients with Hypospadias.
Karabulut R, Turkyilmaz Z, Sonmez K, Kumas G, Ergun S, Ergun M, Basaklar A
This study identifies NR4A2 as one of twenty-four genes upregulated in penile tissue of patients with hypospadias, a common congenital genital anomaly. The findings suggest NR4A2 plays a role in the development of this specific structural birth defect rather than the neurodevelopmental syndrome associated with your child.
- NR4A2 is upregulated in hypospadias tissue alongside twenty-three other genes.
- The study focuses on genital malformation, not neurological or developmental outcomes.
- No clinical data links these expression changes to NR4A2-related neurodevelopmental disorders.
- Findings are specific to penile development and do not inform current care strategies.
Nurr1 expression is regulated by voltage-dependent calcium channels and calcineurin in cultured hippocampal neurons.
Tokuoka H, Hatanaka T, Metzger D, Ichinose H
Neural activity controls Nurr1 levels in brain cells through calcium channels and the calcineurin pathway. This mechanism explains how electrical signals in neurons directly influence the expression of this critical transcription factor.
- Increased neural activity raises Nurr1 protein levels in cultured neurons.
- Decreased neural activity lowers Nurr1 protein levels in cultured neurons.
- Voltage-dependent calcium channels mediate this activity-dependent regulation.
- The calcineurin enzyme is required for increasing Nurr1 expression.
- This process occurs within individual neurons without external signals.
The NR4A2 nuclear receptor is recruited to novel nuclear foci in response to UV irradiation and participates in nucleotide excision repair.
Jagirdar K, Yin K, Harrison M, Lim W, Muscat GE, Sturm RA, Smith AG
This study shows that the NR4A2 protein helps repair DNA damage caused by UV light in skin cells. It identifies specific molecular signals and structural parts of the protein required for this repair function.
- NR4A2 moves to DNA damage sites after UV exposure to assist repair.
- The protein's N-terminal domain is essential for this recruitment process.
- p38 and PARP signaling pathways trigger NR4A2 movement to damage sites.
- Increasing NR4A2 levels speeds up the removal of UV-induced DNA lesions.
A melanocyte lineage program confers resistance to MAP kinase pathway inhibition.
Johannessen CM, Johnson LA, Piccioni F, Townes A, Frederick DT, Donahue MK, Narayan R, Flaherty KT, Wargo JA, Root DE, Garraway LA
This study identifies NR4A2 as a factor that helps melanoma cells resist targeted cancer therapies, but it does not provide information relevant to NR4A2-related developmental syndromes. The research focuses on how this gene contributes to drug resistance in skin cancer rather than its role in brain development or movement disorders.
- NR4A2 helps melanoma cells resist BRAF and MEK inhibitor treatments.
- The study uses cancer cell lines and patient tumor biopsies.
- It does not address NR4A2 syndrome, neurodevelopment, or Parkinson's disease.
- Findings are specific to oncology and MAP kinase pathway resistance.
Cxcl12/Cxcr4 signaling controls the migration and process orientation of A9-A10 dopaminergic neurons.
Yang S, Edman LC, Sánchez-Alcañiz JA, Fritz N, Bonilla S, Hecht J, Uhlén P, Pleasure SJ, Villaescusa JC, Marín O, Arenas E
This study identifies the CXCL12/CXCR4 signaling pathway as a critical mechanism guiding the migration and physical orientation of developing dopaminergic neurons in mice. The findings demonstrate that disrupting this specific molecular signal leads to misplaced neurons and disoriented cellular processes during brain development.
- CXCL12 guides NURR1-positive dopaminergic precursors toward their correct position in the midbrain.
- Blocking CXCR4 signaling causes these neurons to accumulate in incorrect brain regions.
- Genetic deletion of Cxcr4 results in disoriented neuronal processes in mouse models.
- The research focuses exclusively on embryonic development stages in mice.
Detailed expression analysis of regulatory genes in the early developing human neural tube.
Marklund U, Alekseenko Z, Andersson E, Falci S, Westgren M, Perlmann T, Graham A, Sundström E, Ericson J
This study maps gene activity in the developing human brain and finds that Nurr1 is not a unique marker for dopamine neurons, as it also appears in other cell types. It confirms that basic developmental gene patterns are similar between humans and mice but highlights specific differences in how spinal cord motor neurons form.
- Nurr1 expression extends beyond dopamine neurons to other midbrain cell types in humans.
- Human spinal cord motor neurons arise from two distinct progenitor populations.
- Gene patterns are largely conserved between humans, mice, and chickens.
- Findings refine how researchers identify specific neuron subtypes in human development.
NR4A nuclear receptors in immunity and atherosclerosis.
Hamers AA, Hanna RN, Nowyhed H, Hedrick CC, de Vries CJ
This review examines how NR4A nuclear receptors influence immune cell development and vascular health in the context of atherosclerosis. It highlights that specific receptors like Nur77 and Nurr1 reduce arterial plaque in mice, while NOR-1 increases it.
- NR4A receptors regulate immune cell differentiation and endothelial function.
- Nur77 and Nurr1 attenuate atherosclerosis in mouse models.
- NOR-1 aggravates vascular lesion formation in mice.
- The paper focuses on cardiovascular inflammation, not neurodevelopment.
Analysis of FOS, BTG2, and NR4A in the function of renal medullary hypertension.
Wu YB, Zang WD, Yao WZ, Luo Y, Hu B, Wang L, Liang YL
This study found that genes involved in blood vessel formation and immune cell activity, including NR4A2, are changed in kidney tissue from people with high blood pressure. These changes may contribute to the development of hypertension in the kidney's inner part.
- NR4A2 is linked to blood vessel and immune system changes in kidney hypertension
- Other NR4A family genes (NR4A1, NR4A3) also show changes in this condition
- Many genetic variations (SNPs) exist in NR4A2 and related genes
- The findings point to possible new treatment targets for kidney-related high blood pressure
- The study focuses on kidney tissue, not brain or developmental aspects of NR4A2
Lmx1a encodes a rostral set of mesodiencephalic dopaminergic neurons marked by the Wnt/B-catenin signaling activator R-spondin 2.
Hoekstra EJ, von Oerthel L, van der Heide LP, Kouwenhoven WM, Veenvliet JV, Wever I, Jin YR, Yoon JK, van der Linden AJ, Holstege FC, Groot Koerkamp MJ, Smidt MP
This study identifies Lmx1a as a critical regulator for a specific subset of dopaminergic neurons, showing that it controls their development by activating the Wnt signaling pathway through R-spondin 2. Loss of Lmx1a leads to reduced expression of key developmental genes and results in neuronal deficits that mirror those seen when R-spondin 2 is missing.
- Lmx1a regulates Nurr1 and other genes essential for dopaminergic neuron development.
- Lmx1a activates R-spondin 2, a key driver of Wnt/b-catenin signaling in these neurons.
- Loss of Lmx1a causes specific deficits in rostral-lateral dopaminergic neuronal subsets.
- R-spondin 2 deficiency partially replicates the neuronal defects caused by Lmx1a loss.
Activation of developmental nuclear fibroblast growth factor receptor 1 signaling and neurogenesis in adult brain by α7 nicotinic receptor agonist.
Narla ST, Klejbor I, Birkaya B, Lee YW, Morys J, Stachowiak EK, Prokop D, Bencherif M, Stachowiak MK
An experimental drug activates a specific receptor in adult mouse brains to stimulate the growth of new neurons, including those that produce dopamine. This process relies on signaling pathways involving Nurr1 and FGFR1, which are relevant to brain development and repair.
- The drug TC-7020 triggers new neuron formation in adult mice via alpha-7 nicotinic receptors.
- New neurons appear in the substantia nigra with a predopaminergic Nurr1+ phenotype.
- Mechanisms involve nuclear accumulation of FGFR1 and activation of neurogenic signaling.
- The study uses mouse models and cell cultures, not human participants.
MicroRNA profiling and the role of microRNA-132 in neurodegeneration using a rat model.
Lungu G, Stoica G, Ambrus A
This rat study shows that elevated levels of microRNA-132 reduce Nurr1 protein, which subsequently lowers BDNF and may impair midbrain dopaminergic neurons. The findings suggest a specific molecular pathway involving miR-132, Nurr1, and BDNF in neurodegeneration.
- The study uses a spontaneous rat model of autosomal recessive neurodegeneration.
- MicroRNA-132 levels are significantly increased in affected rats.
- Nurr1 protein expression decreases when miR-132 is elevated.
- BDNF levels drop as a downstream effect of reduced Nurr1.
- Results link miR-132 to dopaminergic neuron development issues.
Nurr1 represses tyrosine hydroxylase expression via SIRT1 in human neural stem cells.
Kim TE, Seo JS, Yang JW, Kim MW, Kausar R, Joe E, Kim BY, Lee MA
This study shows that Nurr1 regulates the tyrosine hydroxylase gene differently depending on cell type, acting as a repressor in neural stem cells via SIRT1. It identifies specific molecular mechanisms by which Nurr1 interacts with SIRT1 to fine-tune dopamine-related gene expression during development.
- Nurr1 represses tyrosine hydroxylase in human neural stem cells via SIRT1.
- Nurr1 stimulates the same gene in differentiated dopaminergic-like cells.
- SIRT1 nuclear localization determines whether Nurr1 activates or represses transcription.
- Mutation of the NBRE-A binding site relieves this repression.
Nuclear receptor-mediated regulation of lipid droplet-associated protein gene expression in adipose tissue.
Christian M
This study examines how nuclear receptors, including NURR1, regulate lipid storage in fat cells and has no direct application to NR4A2-related neurodevelopmental syndromes. The research focuses on metabolic processes in adipose tissue rather than brain development or dopaminergic function.
- NURR1 is present in adipose tissue alongside other nuclear receptors like PPARγ.
- The paper investigates lipid droplet dynamics and fat storage mechanisms.
- Findings relate to obesity and lipodystrophy, not neurological conditions.
- No human genetic data or clinical insights for NR4A2 syndromes are provided.
Cytosolic phospholipase A(2)α and eicosanoids regulate expression of genes in macrophages involved in host defense and inflammation.
Suram S, Silveira LJ, Mahaffey S, Brown GD, Bonventre JV, Williams DL, Gow NA, Bratton DL, Murphy RC, Leslie CC
This study shows that cPLA2α and its products, eicosanoids, control how macrophages respond to fungal infection by turning down some inflammatory genes and boosting others involved in defense and inflammation control. The findings reveal a feedback loop where prostaglandins reduce inflammation and alter gene expression through cAMP signaling.
- cPLA2α shapes macrophage responses to infection
- Prostaglandins reduce key inflammatory genes
- cPLA2α boosts genes that help control inflammation
- Eicosanoids act via cAMP to regulate immune genes
- This pathway balances defense and inflammation
Specification of dopaminergic subsets involves interplay of En1 and Pitx3.
Veenvliet JV, Dos Santos MT, Kouwenhoven WM, von Oerthel L, Lim JL, van der Linden AJ, Koerkamp MJ, Holstege FC, Smidt MP
This study identifies how two specific transcription factors, En1 and Pitx3, interact to guide the development of distinct dopamine neuron subtypes in mice. The research demonstrates that these proteins work together to activate genes necessary for midbrain dopamine neurons while simultaneously repressing alternative developmental pathways.
- En1 and Pitx3 cooperate to induce gene expression in developing midbrain dopamine neurons.
- Pitx3 antagonizes En1 activity to specify distinct dopamine neuron subtypes in the brain.
- The study uses mouse models to map molecular interactions during neuronal development.
- Findings explain how combinatorial protein actions determine specific dopamine neuron identities.
Correlation of Nr4a2 expression with the neuron progenitors in adult zebrafish brain.
Chen S, Luo GR, Li T, Liu TX, Le W
This study shows that Nr4a2 is present in adult zebrafish brain progenitor cells and declines with age, suggesting a role in dopamine neuron differentiation. The findings link Nr4a2 expression changes to aging and potential neurodegenerative processes in fish models.
- Nr4a2 co-localizes with dopamine neurons in adult zebrafish brain regions.
- Nr4a2 is expressed in neuronal progenitors alongside nestin.
- Nr4a2 expression declines significantly as zebrafish age.
- Results suggest Nr4a2 regulates dopamine neuron differentiation from stem cells.
- Aging-related changes may relate to neurodegenerative disease mechanisms.
NGF-induced cell differentiation and gene activation is mediated by integrative nuclear FGFR1 signaling (INFS).
Lee YW, Stachowiak EK, Birkaya B, Terranova C, Capacchietti M, Claus P, Aletta JM, Stachowiak MK
Nerve growth factor drives neuronal differentiation by moving FGFR1 proteins into the cell nucleus, where they directly activate Nurr1 and related genes. This nuclear signaling pathway is essential for triggering the physical changes and gene expression required for neurons to mature.
- FGFR1 moves to the nucleus to mediate nerve growth factor effects on neurons.
- Nuclear FGFR1 activates Nurr1 and Nur77 genes critical for neuronal development.
- Blocking nuclear FGFR1 stops neurite outgrowth and key gene activation.
- This study uses PC12 cell lines, not human patients or animal models.
A New Experimental Model for Neuronal and Glial Differentiation Using Stem Cells Derived from Human Exfoliated Deciduous Teeth.
Jarmalavičiūtė A, Tunaitis V, Strainienė E, Aldonytė R, Ramanavičius A, Venalis A, Magnusson KE, Pivoriūnas A
Researchers developed a method to turn stem cells from baby teeth into neurons and glial cells in the lab. The study confirms these cells can express markers for dopaminergic neurons, including Nurr1 (NR4A2), but does not test any treatments or analyze human patients with NR4A2 syndrome.
- Stem cells from baby teeth differentiate into neuron-like and glial cells in culture.
- Differentiated cells express Nurr1, a marker for dopaminergic neurons.
- The study establishes an in vitro model but tests no therapies.
- No human clinical data or patient outcomes are reported.