Correction: Direct Regulation of Pitx3 Expression by Nurr1 in Culture and in Developing Mouse Midbrain.
Volpicelli F, De Gregorio R, Pulcrano S, Perrone-Capano C, di Porzio U, Bellenchi GC
Nurr1 directly controls the expression of Pitx3, a gene critical for the development of dopamine-producing neurons in the midbrain. This interaction is essential for proper brain development and may explain some features of NR4A2-related disorders.
- Nurr1 regulates Pitx3, a key gene for dopamine neurons
- This regulation occurs in developing mouse midbrain
- Disruption may contribute to NR4A2-related neurological symptoms
- Supports Nurr1's role in midbrain development and function
Circulating mRNAs are differentially expressed in pregnancies with severe placental insufficiency and at high risk of stillbirth.
Hannan NJ, Stock O, Spencer R, Whitehead C, David AL, Groom K, Petersen S, Henry A, Said JM, Seeho S, Kane SC, Gordon L, Beard S, Chindera K, Karegodar S, Hiscock R, Pritchard N, Kaitu'u-Lino TJ, Walker SP, Tong S
Circulating mRNA levels in maternal blood can help identify pregnancies with severe placental insufficiency and a very high risk of stillbirth. The gene NR4A2 and others like EMP1 and PGM5 show strong links to this condition and may serve as reliable biomarkers.
- NR4A2 and EMP1 mRNA levels are altered in high-risk pregnancies
- Combining mRNA markers improves detection accuracy
- These markers correlate with fetal acidemia and stillbirth risk
- EMP1 shows the most consistent association across studies
- Blood tests using these mRNAs could help predict stillbirth risk
LncRNA H19 diminishes dopaminergic neuron loss by mediating microRNA-301b-3p in Parkinson's disease via the HPRT1-mediated Wnt/β-catenin signaling pathway.
Jiang J, Piao X, Hu S, Gao J, Bao M
LncRNA H19 protects dopamine-producing brain cells in a mouse model of Parkinson's disease by blocking a microRNA that normally suppresses HPRT1, leading to activation of a key brain-protective signaling pathway. This process helps preserve neurons and maintain dopamine function.
- H19 lncRNA protects dopamine neurons in Parkinson's models
- H19 blocks miR-301b-3p to boost HPRT1 levels
- HPRT1 activates Wnt/β-catenin signaling for neuron survival
- This pathway supports key genes needed for dopamine neuron development
- Findings suggest a potential therapeutic target for neurodegeneration
Dysfunctional Nurr1 promotes high glucose-induced Müller cell activation by up-regulating the NF-κB/NLRP3 inflammasome axis.
Li W, Liu X, Tu Y, Ding D, Yi Q, Sun X, Wang Y, Wang K, Zhu M, Mao J
Nurr1, a protective protein in retinal cells, becomes less active under high glucose conditions, leading to increased inflammation and damage in diabetic retinopathy. Boosting Nurr1 activity with a drug reduced retinal cell loss in diabetic mice, suggesting a potential treatment strategy.
- Nurr1 normally reduces inflammation in retinal cells
- High glucose in diabetes turns off Nurr1
- Inactive Nurr1 triggers harmful inflammation
- A drug that activates Nurr1 protected retinal cells
- Targeting Nurr1 may help treat diabetic eye disease
The transcription factor Nurr1 is upregulated in amyotrophic lateral sclerosis patients and SOD1-G93A mice.
Valsecchi V, Boido M, Montarolo F, Guglielmotto M, Perga S, Martire S, Cutrupi S, Iannello A, Gionchiglia N, Signorino E, Calvo A, Fuda G, Chiò A, Bertolotto A, Vercelli A
Nurr1, a protein involved in reducing brain inflammation, increases early in ALS patients and mice, suggesting it may be part of the body's natural defense against disease progression. Although this response is not strong enough to stop ALS, Nurr1 could serve as a marker for early disease and a target for future treatments.
- Nurr1 levels rise in ALS patients and mouse models
- Nurr1 reduces inflammation and boosts protective brain factors
- It activates early, possibly as a natural defense
- May help detect ALS before symptoms appear
- Could guide new anti-inflammatory treatments
α-Synuclein Negatively Regulates Nurr1 Expression Through NF-κB-Related Mechanism.
Jia C, Qi H, Cheng C, Wu X, Yang Z, Cai H, Chen S, Le W
Alpha-synuclein reduces Nurr1 levels by blocking NF-κB, a key regulator of Nurr1 gene activity, which may contribute to dopamine neuron damage in Parkinson’s disease. This mechanism highlights a direct link between a major Parkinson’s protein and the loss of a protective factor in brain cells.
- Alpha-synuclein lowers Nurr1 levels in brain cells
- It works by suppressing NF-κB activity
- NF-κB normally helps turn on the Nurr1 gene
- This may explain dopamine neuron loss in Parkinson’s
- Suggests new targets for protecting brain cells
The Critical Role of Nurr1 as a Mediator and Therapeutic Target in Alzheimer's Disease-related Pathogenesis.
Jeon SG, Yoo A, Chun DW, Hong SB, Chung H, Kim JI, Moon M
Nurr1, a protein linked to brain health and dopamine regulation, may help protect against Alzheimer's disease by reducing inflammation and supporting neuron survival, suggesting it could be a target for future treatments.
- Nurr1 protects brain cells from damage and inflammation
- It supports cognitive function and dopamine production
- Low Nurr1 levels may worsen Alzheimer's pathology
- Boosting Nurr1 could be a new treatment strategy
- Research is ongoing to develop Nurr1-targeted therapies
In search of common developmental and evolutionary origin of the claustrum and subplate.
Bruguier H, Suarez R, Manger P, Hoerder-Suabedissen A, Shelton AM, Oliver DK, Packer AM, Ferran JL, García-Moreno F, Puelles L, Molnár Z
The claustrum and subplate may share a common developmental and evolutionary origin, with similar gene expression, early birthdates, and cell migration patterns across mammals, suggesting they arise from related ancestral cell populations.
- Claustrum and subplate share early developmental origins
- Similar gene expression, including NR4A2/Nurr1, in both regions
- Both form early in development with comparable migration patterns
- Persistent subplate cells in primates may be evolutionarily linked to claustrum
- Findings suggest shared ancestry across amniotes
De novo variants of NR4A2 are associated with neurodevelopmental disorder and epilepsy.
Singh S, Gupta A, Zech M, Sigafoos AN, Clark KJ, Dincer Y, Wagner M, Humberson JB, Green S, van Gassen K, Brandt T, Schnur RE, Millan F, Si Y, Mall V, Winkelmann J, Gavrilova RH, Klee EW, Engleman K, Safina NP, Slaugh R, Bryant EM, Tan WH, Granadillo J, Misra SN, Schaefer GB, Towner S, Brilstra EH, Koeleman BPC
De novo variants in the NR4A2 gene cause neurodevelopmental disorders and epilepsy, with affected children showing developmental delay, low muscle tone, and seizures. These genetic changes are likely responsible for the observed symptoms and are not inherited from parents.
- NR4A2 variants cause developmental delay and epilepsy
- Variants are new (de novo) and not inherited
- Six out of nine patients have seizures
- One variant disrupts RNA splicing
- NR4A2 is a confirmed disease gene for these conditions
Striatal Nurr1, but not FosB expression links a levodopa-induced dyskinesia phenotype to genotype in Fisher 344 vs. Lewis hemiparkinsonian rats.
Steece-Collier K, Collier TJ, Lipton JW, Stancati JA, Winn ME, Cole-Strauss A, Sellnow R, Conti MM, Mercado NM, Nillni EA, Sortwell CE, Manfredsson FP, Bishop C
In rats, the gene NR4A2 (Nurr1) in the striatum is strongly linked to levodopa-induced dyskinesia (LID), with higher levels found only in rats that develop LID, even when dopamine release and dyskinesia severity are the same. This suggests Nurr1 may be a key player in LID development, not just a bystander, and could point to new treatment targets. The study highlights a new animal model to explore why some animals resist dyskinesia despite similar brain changes.
- NR4A2/Nurr1 levels in the striatum predict LID in rats
- Nurr1 protein increases only with chronic LID, not acute
- FosB changes don’t reliably predict LID, challenging old assumptions
- F344 vs. Lewis rats offer a model to study natural LID resistance
- Nurr1 may be a new target for preventing or treating LID
The Transcription Factor NR4A2 Plays an Essential Role in Driving Prolactin Expression in Female Pituitary Lactotropes.
Peel MT, Ho Y, Liebhaber SA
NR4A2 is a key regulator that boosts prolactin production in female pituitary cells, working alongside another transcription factor to turn on the prolactin gene. It helps release RNA polymerase into the gene body, enabling efficient hormone expression.
- NR4A2 enhances prolactin gene expression in pituitary cells
- NR4A2 works with POU1F1 to activate prolactin production
- NR4A2 helps release RNA polymerase into the gene body
- This mechanism is essential for proper lactotrope function
- Findings reveal a new layer in hormone cell development
Genetic and Epigenetic Modification of Rat Liver Progenitor Cells via HNF4α Transduction and 5' Azacytidine Treatment: An Integrated miRNA and mRNA Expression Profile Analysis.
Bolleyn J, Rombaut M, Nair N, Branson S, Heymans A, Chuah M, VandenDriessche T, Rogiers V, De Kock J, Vanhaecke T
This study in rat liver cells shows that manipulating the HNF4α gene and using a drug that alters DNA methylation can change how cells grow and mature, with specific microRNAs and genes like NR4A2 involved in these processes. The findings suggest potential ways to influence cell development that could inform future therapies for liver-related conditions.
- HNF4α and DNA methylation changes affect liver cell maturation
- NR4A2 is linked to cell viability via microRNA regulation
- Combining HNF4α and DNA-modifying drugs may alter cell growth and death
- MicroRNA changes predict impacts on cell cycle and differentiation
- Findings may guide future strategies for liver cell reprogramming
Transcriptomic Profiling of Circular RNA in Different Brain Regions of Parkinson's Disease in a Mouse Model.
Jia E, Zhou Y, Liu Z, Wang L, Ouyang T, Pan M, Bai Y, Ge Q
This study found that circular RNAs (circRNAs) are altered in specific brain regions of a mouse model of Parkinson's disease, with one circRNA pathway linked to NR4A2, a gene associated with neurodevelopment and brain function. These changes may contribute to Parkinson's disease mechanisms, particularly through pathways involved in neuron health and signaling.
- Specific circRNAs are altered in Parkinson's mouse brain regions
- One circRNA-miRNA-NR4A2 pathway may influence Parkinson's disease
- Changes affect key brain pathways like neuron signaling and survival
- Findings may help explain Parkinson's disease development
- NR4A2 is directly involved in the identified regulatory network
A monolayer hiPSC culture system for autophagy/mitophagy studies in human dopaminergic neurons.
Stathakos P, Jiménez-Moreno N, Crompton LA, Nistor PA, Badger JL, Barbuti PA, Kerrigan TL, Randall AD, Caldwell MA, Lane JD
This study developed a reliable method to grow human dopaminergic neurons from stem cells in a flat, single-layer format that is ideal for studying autophagy and mitophagy—key cellular cleanup processes linked to Parkinson’s disease. The neurons show strong signs of proper development and function, making them useful for testing potential treatments.
- Creates a stable, flat culture of human dopaminergic neurons
- Ideal for studying autophagy and mitophagy in Parkinson’s-relevant cells
- Neurons show proper development and function for research use
- Enables testing of drugs that boost cellular cleanup processes
Striatal Nurr1 Facilitates the Dyskinetic State and Exacerbates Levodopa-Induced Dyskinesia in a Rat Model of Parkinson's Disease.
Sellnow RC, Steece-Collier K, Altwal F, Sandoval IM, Kordower JH, Collier TJ, Sortwell CE, West AR, Manfredsson FP
Nurr1, a brain protein, becomes abnormally active in the striatum of rats with levodopa-induced dyskinesia (LID), and this overactivity directly causes LID symptoms and brain changes linked to LID. In rats, forcing Nurr1 expression even in those normally resistant to LID triggers severe dyskinesia, and blocking Nurr1 activity reduces symptoms. The same protein is also found in the brains of Parkinson’s patients on levodopa.
- Nurr1 overactivity causes LID in rats, even in resistant ones
- Nurr1 changes brain cell activity and structure linked to LID
- Nurr1 is found in Parkinson’s patients on levodopa
- Blocking Nurr1 may reduce LID symptoms
- Nurr1 is a promising target for new LID treatments
Nurr1Cd11bcre conditional knockout mice display inflammatory injury to nigrostriatal dopaminergic neurons.
Dong J, Liu X, Wang Y, Cai H, Le W
When NURR1 is removed from microglia in mice, these immune cells become overactive and more damaging, especially under inflammatory stress. This leads to loss of dopamine-producing neurons and protein clumps linked to Parkinson’s disease, showing that NURR1 in microglia protects brain cells from inflammation-driven damage.
- NURR1 in microglia protects dopamine neurons from inflammation
- Losing NURR1 in microglia worsens brain inflammation
- Inflammation triggers dopamine neuron loss and Parkinson’s-like changes
- This supports targeting microglial NURR1 for Parkinson’s therapies
Gene discovery for high-density lipoprotein cholesterol level change over time in prospective family studies.
Feitosa MF, Lunetta KL, Wang L, Wojczynski MK, Kammerer CM, Perls T, Schupf N, Christensen K, Murabito JM, Province MA
This study found new genetic links to how HDL cholesterol changes over time, including a novel gene called GRID1 and several others potentially involved in lipid metabolism and cardiovascular health. Some of these genes are near or within NR4A2, a gene associated with neurological and metabolic conditions.
- New genes linked to HDL-C changes over time identified
- NR4A2 is near a suggestive locus (LINC01876-NR4A2)
- Some genes affect lipid pathways and cardiovascular health
- Findings may inform metabolic and heart health risks
3D Bioprinting Pluripotent Stem Cell Derived Neural Tissues Using a Novel Fibrin Bioink Containing Drug Releasing Microspheres.
Sharma R, Smits IPM, De La Vega L, Lee C, Willerth SM
This study developed a 3D-printed neural tissue model using human stem cells and a special fibrin gel that releases drugs to guide brain cell development. The printed tissues successfully formed dopamine-producing neurons and showed key markers of midbrain development, including NURR1, which is directly linked to NR4A2-related syndrome. The approach could help test treatments for neurological disorders involving dopamine neurons.
- 3D-printed neural tissues form dopamine neurons from stem cells
- NURR1, a key gene in NR4A2 syndrome, was expressed
- Drug-releasing microspheres guided neuron development
- Tissues showed high cell survival and proper neural markers
- Model may help test therapies for NR4A2-related conditions
TGFβ and Wnt Signaling Pathways Cooperatively Enhance Early Dopaminergic Differentiation of the Unrestricted Somatic Stem Cells.
Akhlaghpour A, Parvaneh Tafreshi A, Roussa E, Bernard C, Zeynali B
TGFβ and Wnt signaling work together to boost the development of dopamine-producing brain cells from adult stem cells, with both pathways needed for proper early differentiation.
- TGFβ and Wnt pathways together promote dopamine cell formation
- Blocking either pathway reduces key markers of dopamine development
- Nurr-1 and β-catenin levels depend on both pathways being active
- This cooperation is critical in early stages of dopamine neuron creation
Change of Nurr1 expression in mouse hippocampal CA3 region following excitotoxic neuronal damage.
Lee CH
Nurr1 protein levels rise quickly in the mouse hippocampus after excitotoxic damage, suggesting it plays a role in the brain's response to injury. Levels peak early and then drop as neurons degenerate.
- Nurr1 increases within 6–12 hours after brain injury
- Peak Nurr1 levels precede significant neuron loss
- Nurr1 may help protect or respond to brain damage
- Changes occur in the hippocampus, a memory-related area
- Findings suggest Nurr1 could be a target for treatment
Loss-of-Function Mutations in NR4A2 Cause Dopa-Responsive Dystonia Parkinsonism.
Wirth T, Mariani LL, Bergant G, Baulac M, Habert MO, Drouot N, Ollivier E, Hodžić A, Rudolf G, Nitschke P, Rudolf G, Chelly J, Tranchant C, Anheim M, Roze E
Loss-of-function mutations in the NR4A2 gene cause a neurological condition that starts with mild intellectual disability in childhood and later leads to dystonia and parkinsonism in early adulthood. These mutations result in reduced function of the NR4A2 protein, which is critical for dopamine neuron development and function.
- NR4A2 mutations cause early-onset dystonia parkinsonism
- Symptoms appear years after initial developmental issues
- Brain scans show normal structure but reduced dopamine function
- Genetic testing for NR4A2 should be considered in unexplained cases
- These mutations are not inherited in these families (de novo)
Pharmacological Stimulation of Nurr1 Promotes Cell Cycle Progression in Adult Hippocampal Neural Stem Cells.
Moon H, Jeon SG, Kim JI, Kim HS, Lee S, Kim D, Park S, Moon M, Chung H
Stimulating the Nurr1 protein with the drug amodiaquine helps adult brain stem cells progress through their cell division cycle, which may boost the creation of new neurons in the hippocampus. This effect occurs by turning on growth-promoting genes and turning off cell cycle brakes.
- Amodiaquine activates Nurr1 to speed up neural stem cell division
- It increases key cell growth markers like PCNA and MCM5
- It reduces levels of cell cycle inhibitors p27KIP1 and p57KIP2
- The effect is seen in both lab cells and mouse brains
- This suggests a potential way to enhance brain repair in NR4A2-related conditions
NURR1 and ERR1 Modulate the Expression of Genes of a DRD2 Coexpression Network Enriched for Schizophrenia Risk.
Torretta S, Rampino A, Basso M, Pergola G, Di Carlo P, Shin JH, Kleinman JE, Hyde TM, Weinberger DR, Masellis R, Blasi G, Pennuto M, Bertolino A
NURR1 and ERR1 are transcription factors that regulate a network of genes linked to dopamine D2 receptors, which are involved in schizophrenia. In people with schizophrenia, levels of NURR1 and ERR1 are reduced, especially in those treated with antipsychotics, suggesting these factors play a role in treatment response.
- NURR1 and ERR1 control genes in a schizophrenia-linked network
- Lower NURR1/ERR1 levels seen in schizophrenia patients
- NURR1 levels drop with antipsychotic treatment
- This network may explain how genetic risks affect schizophrenia
- NURR1 links dopamine signaling to gene regulation
Developmental Co-expression of Vglut2 and Nurr1 in a Mes-Di-Encephalic Continuum Preceeds Dopamine and Glutamate Neuron Specification.
Dumas S, Wallén-Mackenzie Å
Early in development, neurons in the midbrain and diencephalon co-express VGLUT2 and NURR1, suggesting a shared origin for both dopamine and glutamate neurons. This co-expression happens before these neurons fully specialize, and may help explain the diversity of neuron types in the brain.
- VGLUT2 and NURR1 are co-expressed early in brain development
- This co-expression may define a common precursor for dopamine and glutamate neurons
- Some dopamine neuron subtypes form early, before full maturation
- Findings support a developmental continuum in the midbrain-diencephalon region
Transcriptomic Characterization of the Human Insular Cortex and Claustrum.
Ibrahim C, Le Foll B, French L
The study identifies unique gene activity in the human insula and claustrum, with NR4A2 specifically expressed in the claustrum. The insula shows strong links to mood, learning, and dopamine signaling, while the claustrum is tied to intellectual disability, epilepsy, and cellular cleanup processes. These findings help explain the biological roles of these brain regions and may inform future treatments for related disorders.
- NR4A2 is specifically expressed in the claustrum
- Insula genes are linked to mood, learning, and dopamine
- Claustrum genes relate to epilepsy and intellectual disability
- Claustrum markers are also active in the insula during development
- Findings may guide therapies for brain disorders
Altered Nurr1 protein expression in the hippocampal CA1 region following transient global cerebral ischemia.
Park JH, Ahn JH, Kim DW, Lee TK, Park CW, Park YE, Lee JC, Lee HA, Yang GE, Won MH, Lee CH
Nurr1 levels in the hippocampus drop after brain oxygen deprivation, then rise again in brain immune cells, which may be linked to neuron damage in the area most affected by stroke. This suggests Nurr1 plays a role in brain injury response and could be a target for protecting neurons.
- Nurr1 drops in hippocampus neurons after oxygen loss
- Nurr1 returns in brain immune cells days later
- Changes happen only in the CA1 region, where neurons die
- Nurr1 may help protect or repair brain tissue
- This process could be targeted to prevent neuron loss
Structural basis of binding of homodimers of the nuclear receptor NR4A2 to selective Nur-responsive DNA elements.
Jiang L, Dai S, Li J, Liang X, Qu L, Chen X, Guo M, Chen Z, Chen L, Wei H, Chen Y
NR4A2 binds to specific DNA sequences as a dimer, and this study reveals the detailed structure of how two NR4A2 proteins interact with DNA, which helps explain how the protein regulates gene activity in the brain and nervous system.
- NR4A2 forms dimers on certain DNA sequences to control gene activity
- The dimer structure depends on specific DNA shape and protein interactions
- Mutations in key residues disrupt dimer formation and DNA binding
- This structural insight helps explain how NR4A2 regulates genes in development and disease
- Findings may guide future therapies targeting NR4A2 function
The transcription factor FoxM1 activates Nurr1 to promote intestinal regeneration after ischemia/reperfusion injury.
Zu G, Guo J, Zhou T, Che N, Liu B, Wang D, Zhang X
FoxM1 boosts intestinal healing after injury by turning on Nurr1, a gene linked to cell growth. This pathway could be targeted to treat intestinal damage in people, including those with NR4A2-related conditions.
- FoxM1 activates Nurr1 to help gut cells regenerate
- Low FoxM1 and Nurr1 levels are seen in human intestinal injury
- Boosting this pathway may improve healing after gut damage
- Nurr1 is the same protein affected in NR4A2-related syndrome
Epigenetic Regulation of the Ontogenic Expression of the Dopamine Transporter.
Green AL, Eid A, Zhan L, Zarbl H, Guo GL, Richardson JR
The dopamine transporter (DAT) increases in the brain during early development, and this growth is controlled by epigenetic changes, including shifts in histone acetylation and the activity of key regulatory proteins. These findings suggest that early-life epigenetic mechanisms shape dopamine signaling, which may be relevant to neurodevelopmental conditions like autism and ADHD.
- DAT levels rise in the brain during early development
- Epigenetic changes regulate DAT expression over time
- Histone acetylation and transcription factors like Nurr1 are involved
- These mechanisms may influence neurodevelopmental disorders
- Potential for future therapies targeting epigenetic pathways