Vascular endothelial growth factor-regulated gene expression in endothelial cells: KDR-mediated induction of Egr3 and the related nuclear receptors Nur77, Nurr1, and Nor1.
Liu D, Jia H, Holmes DI, Stannard A, Zachary I
Vascular endothelial growth factor (VEGF) activates genes in blood vessel cells that include NR4A2 (also called Nurr1), a gene linked to neurodevelopmental disorders. This activation happens through a specific receptor (KDR) and involves calcium and protein pathways, suggesting potential targets for influencing NR4A2 activity.
- VEGF turns on NR4A2 (Nurr1) and related genes in blood vessel cells
- This process depends on the KDR receptor and calcium signaling
- NR4A2 protein levels increase and become more active after VEGF stimulation
- These genes may be early drivers of blood vessel growth and function
- The findings suggest possible ways to influence NR4A2 activity
Involvement of Nurr1 in specifying the neurotransmitter identity of ventral midbrain dopaminergic neurons.
Smits SM, Ponnio T, Conneely OM, Burbach JP, Smidt MP
Nurr1 is essential for turning on key dopamine-making genes in midbrain neurons during development, including those for dopamine transport and storage, but not for a different enzyme involved in dopamine production. Without Nurr1, these neurons fail to become fully functional dopamine neurons.
- Nurr1 turns on dopamine-related genes in developing neurons
- DAT and VMAT2 need Nurr1 to be expressed
- AADC gene works without Nurr1
- Nurr1 is critical for dopamine neuron identity
- Loss of Nurr1 disrupts dopamine system development
Familial Parkinson's disease: a hint to elucidate the mechanisms of nigral degeneration.
Hattori N, Kobayashi H, Sasaki-Hatano Y, Sato K, Mizuno Y
Mutations in the NR4A2 gene are linked to familial Parkinson's disease and may play a role in the degeneration of dopamine-producing neurons in the brain. While most Parkinson's cases are sporadic, these genetic findings help reveal shared biological pathways that could inform treatments for both inherited and common forms of the disease.
- NR4A2 mutations cause familial Parkinson's disease
- NR4A2 is involved in dopamine neuron survival
- Genes linked to Parkinson's may share common disease pathways
- Understanding NR4A2 helps explain Parkinson's mechanisms
- Findings may lead to treatments for both familial and sporadic PD
The orphan steroid receptor Nur77 family member Nor-1 is essential for early mouse embryogenesis.
DeYoung RA, Baker JC, Cado D, Winoto A
Nor-1, a gene related to NR4A2, is essential for early mouse development, with its absence causing embryonic death around day 8.5 due to failed gastrulation and abnormal cell development.
- Nor-1 is critical for early embryonic development in mice
- Loss of Nor-1 leads to failure in gastrulation and embryonic death
- Defects include delayed development and abnormal mesoderm formation
- Nor-1 is highly expressed during early embryogenesis
- This highlights a key role in fundamental developmental processes
Rapid increase of Nurr1 expression in the substantia nigra after 6-hydroxydopamine lesion in the striatum of the rat.
Ojeda V, Fuentealba JA, Galleguillos D, Andrés ME
After damaging dopamine-producing neurons in rats, the brain rapidly increases production of the Nurr1 protein in the substantia nigra, suggesting Nurr1 helps the brain compensate for dopamine loss. This response may be part of the brain's natural attempt to restore dopamine balance.
- Nurr1 levels rise quickly after dopamine neuron damage
- Increased Nurr1 occurs in both sides of the brain after one-sided injury
- Nurr1 may help the brain adapt to low dopamine levels
- Nurr1 is found in unexpected brain areas, including the striatum
- Nurr1 location inside cells may affect its function
Nurr1 regulates dopamine synthesis and storage in MN9D dopamine cells.
Hermanson E, Joseph B, Castro D, Lindqvist E, Aarnisalo P, Wallén A, Benoit G, Hengerer B, Olson L, Perlmann T
Nurr1 is essential for dopamine production and storage in dopamine neurons, directly controlling key proteins needed to make and store dopamine. Without Nurr1, these functions fail, which explains why Nurr1 mutations cause severe dopamine-related disorders.
- Nurr1 controls dopamine synthesis and storage
- Nurr1 boosts AADC and VMAT2 proteins
- Dopamine levels drop without Nurr1
- Nurr1 must be continuously present to maintain VMAT2
- Nurr1 loss disrupts dopamine function in embryos
Elevated locomotor activity without altered striatal dopamine contents in Nurr1 heterozygous mice after acute exposure to methamphetamine.
Bäckman C, You ZB, Perlmann T, Hoffer BJ
Mice with one missing copy of the Nurr1 gene show increased movement after methamphetamine, even though their brain dopamine levels are normal. This suggests that Nurr1 deficiency affects how dopamine is used in the brain, not just how much is present.
- One copy of Nurr1 gene missing increases movement in older mice
- Brain dopamine levels unchanged in these mice
- Methamphetamine caused more movement despite normal dopamine
- Possible changes in dopamine release or reuptake may be involved
- Findings may help understand movement issues in NR4A2-related syndrome
Activation incarnate.
Privalsky ML
NR4A2 (Nurr1) can switch into its active shape without needing a chemical signal, which may help control gene activity in the brain and could influence how we treat NR4A2-related disorders.
- NR4A2 naturally activates without needing a drug or signal
- This active shape may affect brain development and function
- Understanding this could lead to new treatments for NR4A2 syndrome
- The discovery reveals how gene switches are turned on
Expression of depolarization-induced immediate early gene proteins in PC12 cells.
Liu W, Feldman JD, Machado HB, Vician LJ, Herschman HR
This study shows that specific immediate early genes, including Nurr-1 (NR4A2), are rapidly activated in response to neuronal depolarization in a cell model. The proteins from these genes appear quickly, peak within hours, and return to baseline, suggesting a role in early brain plasticity responses.
- NR4A2 (Nurr-1) protein peaks 2–4 hours after stimulation
- Other related proteins also rise quickly and return to baseline
- These genes respond to depolarization, not growth factors
- Findings may relate to how neurons adapt after activity
- Cell model used is relevant to neuronal function
Sonic hedgehog and FGF8 collaborate to induce dopaminergic phenotypes in the Nurr1-overexpressing neural stem cell.
Kim TE, Lee HS, Lee YB, Hong SH, Lee YS, Ichinose H, Kim SU, Lee MA
Overexpressing the Nurr1 gene in neural stem cells, combined with Shh and FGF-8 signals, can reliably turn these cells into midbrain dopamine-producing neurons, offering a potential source for cell-based therapies in Parkinson’s disease.
- Nurr1 overexpression makes neural stem cells responsive to dopamine-inducing signals
- Shh and FGF-8 together with Nurr1 drive formation of dopamine neurons
- This method creates a scalable source of dopamine progenitors
- Findings may help develop cell replacement therapies for Parkinson’s
Dopaminergic neuronal differentiation from rat embryonic neural precursors by Nurr1 overexpression.
Kim JY, Koh HC, Lee JY, Chang MY, Kim YC, Chung HY, Son H, Lee YS, Studer L, McKay R, Lee SH
Overexpressing the Nurr1 gene can turn ordinary brain precursor cells into dopamine-producing neurons in a lab setting, but these neurons are not fully mature and do not function well after transplantation. This suggests Nurr1 is key for making dopamine neurons, but other factors are needed for them to work properly in the brain.
- Nurr1 turns brain precursor cells into dopamine neurons in the lab
- Cells make dopamine but are less mature than natural ones
- Transplanted cells survive poorly and don’t improve behavior
- More factors are needed to make functional dopamine neurons
- This helps understand how to grow dopamine cells for therapy
Midbrain dopaminergic neurons: determination of their developmental fate by transcription factors.
Simon HH, Bhatt L, Gherbassi D, Sgadó P, Alberí L
NR4A2 (Nurr1) is a critical gene for the development and function of midbrain dopamine neurons, which are affected in Parkinson's disease. Without Nurr1, these neurons fail to produce dopamine properly, even though they form initially. This gene specifically controls dopamine-related genes and is essential only in midbrain dopamine neurons.
- Nurr1 is essential for dopamine neuron function
- Nurr1 controls genes needed for dopamine production
- Loss of Nurr1 disrupts dopamine neuron identity
- Nurr1 is not needed for other dopamine neurons
- Nurr1 dysfunction may relate to Parkinson's disease
Transcriptional control of dopamine neuron development.
Wallén A, Perlmann T
NR4A2 (Nurr1) is a key transcription factor that helps control the development of dopamine neurons, which are affected in conditions like Parkinson's disease. Research shows that Nurr1, along with other factors like Lmx1b and Pitx3, guides the formation of these neurons during brain development and is essential for their proper function.
- NR4A2/Nurr1 is critical for dopamine neuron development
- Nurr1 works with Lmx1b and Pitx3 to build dopamine neurons
- Understanding Nurr1 helps in creating dopamine neurons from stem cells
- This research may lead to future therapies for dopamine-related disorders
Transcription factors in the development of midbrain dopamine neurons.
Burbach JP, Smits S, Smidt MP
NR4A2 (Nurr1) is essential for midbrain dopamine neurons to produce dopamine and survive during development, working alongside other key genes like Lmx1b and Ptx3. Disrupting these genes impairs the structure and function of dopamine systems, highlighting their critical role in brain development.
- NR4A2 controls dopamine production in midbrain neurons
- NR4A2 works with Lmx1b and Ptx3 for neuron survival
- Ptx3 disruption affects the substantia nigra and brain organization
- Multiple transcription factors must work together for healthy dopamine systems
Decreased ethanol preference and wheel running in Nurr1-deficient mice.
Werme M, Hermanson E, Carmine A, Buervenich S, Zetterström RH, Thorén P, Ogren SO, Olson L, Perlmann T, Brené S
Mice with half the normal amount of the Nurr1 protein show reduced interest in ethanol and less voluntary wheel running, suggesting Nurr1 plays a key role in reward-seeking behaviors. This supports Nurr1 as a likely contributor to addiction-related traits and natural reward behaviors.
- Nurr1 deficiency reduces ethanol preference and wheel running
- Half the Nurr1 protein affects reward-seeking behaviors
- Nurr1 is linked to addiction-related traits in mice
- Human NR4A2 mutations may affect similar brain pathways
- Nurr1 variants may influence reward behavior in people
Structure and function of Nurr1 identifies a class of ligand-independent nuclear receptors.
Wang Z, Benoit G, Liu J, Prasad S, Aarnisalo P, Liu X, Xu H, Walker NP, Perlmann T
Nurr1, a key protein involved in brain development and function, works without needing a chemical signal to activate it. Its structure shows why it doesn’t bind ligands and instead stays active through a stable shape, offering new ideas for treating NR4A2-related disorders.
- Nurr1 functions without needing a ligand to turn on
- Its stable structure keeps it active without external signals
- This explains how NR4A2-related disorders may be regulated
- Offers a path for developing drugs that stabilize Nurr1
- Provides a clear model for how similar proteins work
Parkinson's disease: piecing together a genetic jigsaw.
Dekker MC, Bonifati V, van Duijn CM
Mutations in the NR4A2 gene disrupt a key signaling pathway and contribute to Parkinson's disease, highlighting a distinct biological mechanism that may inform future treatments. This gene is linked to early-onset Parkinson's and shares features with other genetic forms of the disease.
- NR4A2 mutations impair a critical signaling pathway in Parkinson's
- NR4A2 is linked to early-onset Parkinson's, not just late-onset
- Genetic forms of Parkinson's reveal multiple disease pathways
- Understanding NR4A2 helps clarify disease mechanisms beyond protein clumps
- These findings may guide targeted therapies in the future
The control of dopamine neuron development, function and survival: insights from transgenic mice and the relevance to human disease.
Eells JB
Genes like NR4A2 (Nurr1) are essential for the development, function, and survival of dopamine neurons. Disruptions in these genes in mice mirror human conditions such as Parkinson’s disease, offering insights into potential treatments.
- NR4A2/Nurr1 is critical for dopamine neuron development and survival
- Mouse models with NR4A2 disruption show Parkinson’s-like symptoms
- These findings help explain human dopamine-related disorders
- Potential for therapies targeting NR4A2 pathways
- Gene disruptions lead to compensatory changes in brain circuits
Orphan nuclear receptor Nurr1 directly transactivates the promoter activity of the tyrosine hydroxylase gene in a cell-specific manner.
Kim KS, Kim CH, Hwang DY, Seo H, Chung S, Hong SJ, Lim JK, Anderson T, Isacson O
Nurr1 directly turns on the tyrosine hydroxylase (TH) gene, which is essential for dopamine production, in a way that depends on the cell type. This activation happens through specific DNA sequences near the TH gene, with one site (NL3) being especially important for Nurr1 binding and gene activation.
- Nurr1 directly activates the TH gene, critical for dopamine production
- Activation depends on specific DNA sites near the TH gene
- NL3 site is key for Nurr1 binding and gene activation
- Nurr1 does not affect the DBH gene, which controls noradrenaline
- This mechanism helps define dopamine-producing neurons
A common NURR1 polymorphism associated with Parkinson disease and diffuse Lewy body disease.
Zheng K, Heydari B, Simon DK
A common genetic variation in the NURR1 gene increases the risk of Parkinson's disease, especially in people who develop symptoms before age 45. The same variation may also be linked to a related brain disorder called diffuse Lewy body disease.
- A common NURR1 gene variant raises Parkinson's risk
- Higher risk seen in early-onset Parkinson's cases
- Variant linked to diffuse Lewy body disease
- Homozygous form may contribute to disease
- NURR1 plays a key role in dopamine neuron health
Regulation of NGFI-B expression during the ovulatory process.
Park JI, Park HJ, Lee YI, Seo YM, Chun SY
NGFI-B, a gene related to NR4A2 (NURR1), is rapidly turned on in ovarian cells during ovulation in response to hormone signals. This activation depends on a specific enzyme called protein kinase Czeta and may play a key role in the ovulatory process.
- NGFI-B is activated within 1 hour of ovulation signals
- Activation requires protein kinase Czeta
- Other NR4A2-related genes are also activated
- This process occurs in human ovarian cells
- May help explain how ovulation is controlled
The AF-1 domain of the orphan nuclear receptor NOR-1 mediates trans-activation, coactivator recruitment, and activation by the purine anti-metabolite 6-mercaptopurine.
Wansa KD, Harris JM, Yan G, Ordentlich P, Muscat GE
The NR4A family of nuclear receptors, including NURR1 (NR4A2), acts as sensors for genotoxic stress and can be activated by the drug 6-mercaptopurine through their AF-1 domain, which recruits coactivators independently of the ligand-binding domain. This activation occurs without a traditional ligand-binding mechanism, suggesting a unique way these receptors respond to cellular stress.
- NR4A receptors like NURR1 are activated by 6-mercaptopurine via the AF-1 domain
- AF-1 recruits coactivators without needing the ligand-binding domain
- The receptor's structure lacks a typical ligand-binding cleft, making it unique
- Activation may link to cellular stress responses, not traditional hormone signaling
- This suggests a potential pathway for modulating NR4A activity in disease
Identification of the antineoplastic agent 6-mercaptopurine as an activator of the orphan nuclear hormone receptor Nurr1.
Ordentlich P, Yan Y, Zhou S, Heyman RA
6-mercaptopurine, a drug used to treat leukemia and inflammatory diseases, activates the Nurr1 protein, which may explain part of its anti-cancer effects and suggest a new role for Nurr1 in treating blood cancers.
- 6-mercaptopurine activates Nurr1, a protein linked to brain and immune function
- This activation occurs through a specific region in the Nurr1 protein
- Nurr1 may help mediate the drug's anti-cancer effects
- The effect is blocked by components of purine metabolism
- This suggests Nurr1 could be a target for treating leukemia
The human tyrosine hydroxylase gene promoter.
Kessler MA, Yang M, Gollomp KL, Jin H, Iacovitti L
The human tyrosine hydroxylase gene promoter contains regulatory regions that control its activity in dopamine-producing neurons, with key binding sites for NR4A2 (Nurr1) and other transcription factors conserved across humans, mice, and rats. These findings help explain how the gene is turned on in the brain and may inform future therapies targeting dopamine production.
- NR4A2 binding sites are present in the human TH promoter
- Conserved regulatory regions across species suggest functional importance
- Promoter drives gene activity in dopamine neurons
- Findings support targeted gene regulation strategies
- May guide development of therapies for dopamine-related disorders
Dimer-specific potentiation of NGFI-B (Nur77) transcriptional activity by the protein kinase A pathway and AF-1-dependent coactivator recruitment.
Maira M, Martens C, Batsché E, Gauthier Y, Drouin J
NR4A2 (Nurr1) and related proteins act as switches in brain and hormone systems, turning on genes in response to stress signals through a specific dimer form and a key protein region called AF-1. This process depends on a common cellular pathway (PKA) and recruitment of coactivator proteins, which boost gene activity only when the proteins are paired together.
- NR4A2 works best as a dimer, not alone
- Stress signals activate NR4A2 via the PKA pathway
- AF-1 domain is essential for boosting gene activity
- Coactivators like SRC-2 are recruited only to dimers
- This mechanism controls key genes in brain and hormone systems
Hzf-3 expression in the amygdala after establishment of conditioned taste aversion.
Ge H, Chiesa R, Peña de Ortiz S
The gene NR4A2 (also called Nurr1 or HZF-3) becomes active in a specific part of the rat brain's amygdala when a taste is linked to illness, showing it plays a key role in forming aversive memories. This activation only happens when both the taste and illness are paired, not when either occurs alone.
- NR4A2 turns on in the amygdala during aversion learning
- Activation requires both taste and illness stimuli together
- Happens faster in the lateral/basolateral amygdala
- NR4A2 is involved in forming negative memories
- Suggests a role in how the brain learns to avoid harmful things
Mutations in NR4A2 associated with familial Parkinson disease.
Le WD, Xu P, Jankovic J, Jiang H, Appel SH, Smith RG, Vassilatis DK
Mutations in the NR4A2 gene are linked to familial Parkinson's disease and cause a significant drop in NR4A2 mRNA levels, leading to dopaminergic neuron dysfunction. These mutations affect gene activity and are not found in sporadic Parkinson's cases or healthy controls.
- NR4A2 mutations cause familial Parkinson's disease
- Mutations reduce NR4A2 mRNA levels in patients
- Affected individuals show typical Parkinson's symptoms
- NR4A2 mutations disrupt tyrosine hydroxylase gene expression
- No link found to sporadic Parkinson's or healthy controls
The constitutive and inducible expression of Nurr1, a key regulator of dopaminergic neuronal differentiation, in human neural and non-neural cell lines.
Satoh J, Kuroda Y
Nurr1 is naturally present in human neural and non-neural cells and increases when neurons are activated by certain signaling pathways, but it does not clearly turn on key genes linked to dopamine neuron development in the tested cells. This suggests that Nurr1 may need other factors to function properly in human neurons.
- Nurr1 is present in many human cell types under normal conditions
- Nurr1 levels rise in human neurons when activated by specific signals
- Nurr1 did not turn on known dopamine-related genes in lab tests
- Other factors may be needed for Nurr1 to work in human neurons
- This highlights a gap in understanding how Nurr1 functions in human brain cells
Overexpression of midbrain-specific transcription factor Nurr1 modifies susceptibility of mouse neural stem cells to neurotoxins.
Lee MA, Lee HS, Lee HS, Cho KG, Jin BK, Sohn S, Lee YS, Ichinose H, Kim SU
Overexpressing the Nurr1 protein in mouse neural stem cells makes them more sensitive to one toxin (6-OHDA) but more resistant to another (MPP+), suggesting Nurr1 influences how dopamine neurons respond to different neurotoxins. This indicates Nurr1 may affect the risk of dopamine neuron damage in Parkinson’s disease.
- Nurr1 overexpression increases sensitivity to 6-OHDA
- Nurr1 overexpression increases resistance to MPP+
- Different cell death pathways are triggered by each toxin
- Nurr1 may influence vulnerability to Parkinson’s-related damage
- Findings suggest Nurr1 levels could affect disease risk
Genetic engineering of mouse embryonic stem cells by Nurr1 enhances differentiation and maturation into dopaminergic neurons.
Chung S, Sonntag KC, Andersson T, Bjorklund LM, Park JJ, Kim DW, Kang UJ, Isacson O, Kim KS
Forcing the Nurr1 gene to stay active in mouse stem cells dramatically increases the number of dopamine-producing brain cells, which are the type affected in NR4A2-related syndrome. These engineered cells mature into functional dopamine neurons that behave like those in the midbrain, showing promise for future therapies.
- Nurr1 gene boosts dopamine neuron production 4–5 fold
- Engineered neurons make and release dopamine properly
- Cells match key features of midbrain dopamine neurons
- No unwanted neurotransmitters were made
- This method could guide future cell-based treatments
Nurr1-null heterozygous mice have reduced mesolimbic and mesocortical dopamine levels and increased stress-induced locomotor activity.
Eells JB, Lipska BK, Yeung SK, Misler JA, Nikodem VM
Mice with one missing copy of the NR4A2 gene (Nurr1) have lower dopamine levels in brain regions linked to mood and behavior, and show increased movement in response to mild stress. This suggests that even partial loss of NR4A2 function disrupts dopamine systems involved in mental health.
- One copy of NR4A2 loss reduces dopamine in key brain areas
- Increased movement under stress occurs even in young mice
- NR4A2 is critical for dopamine pathways beyond development
- Findings may relate to psychiatric conditions like schizophrenia
- Suggests NR4A2 dysfunction could contribute to behavioral symptoms
Regulation of synaptic plasticity genes during consolidation of fear conditioning.
Ressler KJ, Paschall G, Zhou XL, Davis M
Fear memory formation in mammals involves widespread changes in gene activity across multiple brain regions, not just the amygdala. Specific genes linked to synaptic plasticity are turned on or off at precise times after learning, suggesting a coordinated molecular process underlying long-term memory.
- Memory consolidation activates genes beyond the amygdala
- Nurr-1 and other plasticity genes rise 2–4 hours after learning
- Gene changes align with memory formation, not just stress or shock
- Cytoskeletal and synaptic proteins are key players in memory
- Timing of gene expression is critical for memory stability
Reduced adrenal activation in a rat line selected for high alcohol sensitivity.
Raatesalmi K, Virtanen A, Sarviharju M, Pelto-Huikko And M, Korpi ER
Rats bred to be highly sensitive to alcohol show reduced adrenal gland activity when exposed to alcohol or stress, linked to lower activation of key genes like NURR1. This suggests a biological mechanism for alcohol sensitivity that may relate to human conditions involving adrenal and stress hormone regulation.
- Alcohol-sensitive rats have weaker adrenal responses to alcohol and stress
- Genes like NURR1 show reduced activation in sensitive rats
- Lower adrenal gene activity may explain heightened alcohol sensitivity
- Findings align with human studies on glucocorticoid effects on alcohol response