Differential expression and dynamic changes of murine NEDD9 in progenitor cells of diverse tissues.
Aquino JB, Marmigère F, Lallemend F, Lundgren TK, Villar MJ, Wegner M, Ernfors P
NEDD9 is a protein involved in cell signaling that is active in early stem-like cells during mouse development, particularly in brain and other organ-forming tissues. It is present in cells that give rise to neurons and dopamine-producing cells, but disappears when these cells begin to specialize.
- NEDD9 is found in early stem cells of the brain and other organs
- It is active in cells that become neurons and dopamine-producing cells
- NEDD9 levels drop when cells start to specialize
- Its presence is linked to key developmental proteins like Sox2 and Nurr1
- NEDD9 may help regulate early cell decisions in organ formation
Genotype patterns that contribute to increased risk for or protection from developing heroin addiction.
Nielsen DA, Ji F, Yuferov V, Ho A, Chen A, Levran O, Ott J, Kreek MJ
This study found specific genetic patterns linked to both increased risk and protection from heroin addiction, including variants in the NR4A2 gene, which is also involved in neurological development and function. The results suggest that certain combinations of genetic markers may strongly influence susceptibility to substance use disorders.
- NR4A2 gene variants are linked to heroin addiction risk
- Specific genetic patterns increase or protect against addiction
- Findings may inform future treatments for substance use disorders
- Genetic patterns explain a large portion of addiction risk in the cohort
Gene expression profile of neuronal progenitor cells derived from hESCs: activation of chromosome 11p15.5 and comparison to human dopaminergic neurons.
Freed WJ, Chen J, Bäckman CM, Schwartz CM, Vazin T, Cai J, Spivak CE, Lupica CR, Rao MS, Zeng X
A study of human stem cells turning into dopamine-producing neurons found that a specific region on chromosome 11, called 11p15.5, is highly active during this process. This region includes key genes like TH, IGF2, and CDKN1C, which are important for dopamine neuron development and function, and may play a central role in guiding stem cells to become these specialized brain cells.
- Chromosome 11p15.5 region is highly active during dopamine neuron development
- Genes in this region include TH, IGF2, and CDKN1C, critical for dopamine neurons
- CDKN1C works with Nurr1, the gene mutated in NR4A2-related syndrome
- This region is active in both lab-grown and real human dopamine neurons
- Findings suggest a key regulatory role for 11p15.5 in neuron formation
Social isolation rearing-induced impairment of the hippocampal neurogenesis is associated with deficits in spatial memory and emotion-related behaviors in juvenile mice.
Ibi D, Takuma K, Koike H, Mizoguchi H, Tsuritani K, Kuwahara Y, Kamei H, Nagai T, Yoneda Y, Nabeshima T, Yamada K
Social isolation in young mice impairs the creation of new brain cells in the hippocampus, leading to memory problems and emotional issues. Reduced levels of the Nurr1 gene, which is linked to NR4A2, are tied to these brain changes, suggesting that social interaction supports healthy brain development.
- Social isolation harms new brain cell growth in mice
- Memory and behavior problems follow impaired neurogenesis
- Nurr1 gene levels drop under isolation
- Low Nurr1 may explain brain and behavior issues
- Antidepressants can partially reverse some effects
Heroin abuse is characterized by discrete mesolimbic dopamine and opioid abnormalities and exaggerated nuclear receptor-related 1 transcriptional decline with age.
Horvath MC, Kovacs GG, Kovari V, Majtenyi K, Hurd YL, Keller E
Heroin use in humans causes specific damage to brain reward circuits, particularly reducing a key protein called Nurr1 that controls dopamine function, and this decline worsens with age. The changes are mainly in areas linked to addiction and motivation, not movement, and are tied to both dopamine and opioid system disruptions.
- Heroin use reduces Nurr1, a critical gene for dopamine health
- Nurr1 decline worsens with age in users, worsening brain function
- Dopamine system damage is focused in reward areas, not movement areas
- Opioid receptors in reward circuits are also disrupted
- These changes may explain long-term addiction and aging effects
Expression and function of nr4a2, lmx1b, and pitx3 in zebrafish dopaminergic and noradrenergic neuronal development.
Filippi A, Dürr K, Ryu S, Willaredt M, Holzschuh J, Driever W
Nr4a2 helps control dopamine production in certain zebrafish brain neurons, but most dopamine-producing neurons in the diencephalon do not use it, suggesting other genes take over in these cells. Lmx1b appears to help create the early precursor cells for these diencephalic dopamine neurons, even though it's not found in the mature neurons.
- Nr4a2 is needed for dopamine production in some zebrafish neurons
- Most diencephalic dopamine neurons don’t use Nr4a2
- Lmx1b helps form early precursor cells for diencephalic dopamine neurons
- Pitx3 does not affect diencephalic dopamine clusters in zebrafish
- Zebrafish model reveals evolutionary differences in dopamine system development
Treatment of Parkinson disease with C17.2 neural stem cells overexpressing NURR1 with a recombined republic-deficit adenovirus containing the NURR1 gene.
Li QJ, Tang YM, Liu J, Zhou DY, Li XP, Xiao SH, Jian DX, Xing YG
Engineered neural stem cells that produce NURR1 protein show promise in improving symptoms and brain changes in a rat model of Parkinson's disease, suggesting a potential therapy for NR4A2-related movement disorders.
- NURR1-producing stem cells improved brain and behavior in Parkinson's rats
- The therapy boosted neuron formation from stem cells
- This approach may help treat conditions linked to NR4A2 deficiency
- Results support further study of NURR1-based treatments
Angiotensin-II acute regulation of rapid response genes in human, bovine, and rat adrenocortical cells.
Nogueira EF, Vargas CA, Otis M, Gallo-Payet N, Bollag WB, Rainey WE
This study identifies rapid-response genes activated by angiotensin-II in adrenal cells across humans, cows, and rats, including NR4A2, which is involved in hormone production. The findings suggest these genes are direct targets of angiotensin-II signaling and may regulate aldosterone output. The overlap in gene responses across species highlights key regulators of adrenal function.
- NR4A2 is rapidly activated by angiotensin-II in adrenal cells
- The same genes respond across human, bovine, and rat adrenal cells
- NR4A2 and related genes are direct targets of angiotensin-II signaling
- These genes may control aldosterone production in the adrenal gland
- Findings support NR4A2 as a central player in adrenal hormone regulation
Beneficial effects of dietary omega-3 polyunsaturated fatty acid on toxin-induced neuronal degeneration in an animal model of Parkinson's disease.
Bousquet M, Saint-Pierre M, Julien C, Salem N, Cicchetti F, Calon F
A high intake of omega-3 fatty acids protects mouse brain cells from damage caused by a toxin that mimics Parkinson's disease, preserving key proteins and dopamine levels in brain regions critical for movement control.
- Omega-3 fats prevented neuron loss in the brain's movement control center
- Omega-3s preserved dopamine and related proteins after toxin exposure
- Protection occurred even though dopamine nerve endings in the striatum were not directly affected
- High omega-3 diet reduced damage linked to Parkinson's-like brain degeneration
mRNA expression of activity-regulated cytoskeleton-associated protein (arc) in the amygdala-kindled rats.
Akiyama K, Ishikawa M, Saito A
This study found that the arc gene, which helps reorganize brain connections after activity, is strongly activated in specific brain regions after seizures in rats. The changes in arc mRNA were linked to areas involved in learning and emotion, suggesting it plays a role in how the brain rewires itself after repeated seizures.
- Arc gene activity increases after seizures in rat brains
- Arc mRNA appears in areas linked to memory and emotion
- Changes occur in regions that may be involved in seizure-related brain remodeling
- Arc is tied to synaptic reorganization after brain activity
The glucocorticoid receptor is a co-regulator of the orphan nuclear receptor Nurr1.
Carpentier R, Sacchetti P, Ségard P, Staels B, Lefebvre P
The glucocorticoid receptor (GR) directly interacts with Nurr1 (NR4A2), altering its activity and allowing glucocorticoids to regulate Nurr1 in the brain. This interaction changes how Nurr1 controls gene expression and may open new ways to treat NR4A2-related disorders using existing drugs.
- GR binds to Nurr1 and changes its function in the brain
- Glucocorticoids can now influence Nurr1 activity through this link
- The N-terminal part of Nurr1 is key to this interaction
- Co-regulators like SMRT and SRC2 affect the Nurr1-GR complex
- This could lead to new treatment strategies using steroid drugs
Delta-like 1 participates in the specification of ventral midbrain progenitor derived dopaminergic neurons.
Bauer M, Szulc J, Meyer M, Jensen CH, Terki TA, Meixner A, Kinkl N, Gasser T, Aebischer P, Ueffing M
Delta-like 1 helps control the development of dopamine-producing brain cells in the ventral midbrain, promoting the formation of neurons that express NR4A2, a gene linked to your child’s condition. The protein acts early in development to support the growth of precursor cells and their eventual differentiation into dopamine neurons.
- Dlk1 boosts the creation of NR4A2-expressing dopamine neurons
- Dlk1 supports early progenitor cell growth in the midbrain
- Dlk1 may act as a permissive signal for dopamine neuron development
- Timing matters: Dlk1 works best during early cell expansion
- Findings suggest Dlk1 could influence NR4A2-related brain development
Neural precursors derived from human embryonic stem cells maintain long-term proliferation without losing the potential to differentiate into all three neural lineages, including dopaminergic neurons.
Hong S, Kang UJ, Isacson O, Kim KS
Human stem cell-derived neural precursors can be grown in large quantities for over a year while still retaining the ability to become all types of brain cells, including dopamine-producing neurons essential for movement and behavior. These cells remain stable through freezing and thawing, making them a reliable source for research and potential therapies.
- Neural precursors from human stem cells expand massively in culture
- They maintain ability to become dopamine neurons and other brain cells
- Cells stay functional after long-term freezing and thawing
- Potential source for treating Parkinson’s and other brain disorders
- Provides a stable, renewable supply for research and therapy
Association analysis of 15 polymorphisms within 10 candidate genes for antisocial behavioural traits.
Prichard ZM, Jorm AF, Mackinnon A, Easteal S
Certain genetic variations in the NR4A2 gene are linked to antisocial behaviors in women, suggesting that this gene may play a role in regulating social behavior. The findings highlight NR4A2 as a potential factor in behavioral differences, particularly in females.
- NR4A2 gene variants associated with antisocial traits in women
- NR4A2 is a transcription factor involved in brain development
- Findings suggest NR4A2 may influence social behavior regulation
- Results point to possible biological pathways in behavioral variation
NR4A nuclear orphan receptors: protective in vascular disease?
Pols TW, Bonta PI, de Vries CJ
NR4A nuclear receptors, including Nurr1 (NR4A2), play important roles in metabolism and in cells that contribute to vascular disease, suggesting they may influence conditions like atherosclerosis. These receptors are involved in processes such as inflammation and energy regulation within blood vessels.
- NR4A receptors regulate metabolism and energy use
- They affect macrophages, endothelial, and smooth muscle cells in blood vessels
- NR4A2 (Nurr1) is linked to vascular disease development
- These receptors may be targets for treating vascular conditions
9-Methyl-beta-carboline up-regulates the appearance of differentiated dopaminergic neurones in primary mesencephalic culture.
Hamann J, Wernicke C, Lehmann J, Reichmann H, Rommelspacher H, Gille G
9-Methyl-beta-carboline boosts the development of dopamine-producing brain cells in lab-grown tissue, potentially protecting and enhancing these cells, which may inform future treatments for NR4A2-related disorders involving dopamine neuron dysfunction.
- 9-Methyl-beta-carboline increases dopamine neuron formation in lab cultures
- It protects neurons and reduces cell death and inflammation
- It boosts key genes needed for dopamine neuron development
- It may help restore dopamine function, though not significantly in this study
- The exact source of new neurons remains unclear
A Nurr1 point mutant, implicated in Parkinson's disease, uncouples ERK1/2-dependent regulation of tyrosine hydroxylase transcription.
Jacobsen KX, MacDonald H, Lemonde S, Daigle M, Grimes DA, Bulman DE, Albert PR
A specific mutation in the NURR1 gene, linked to Parkinson's disease, disrupts the protein's ability to activate the gene for tyrosine hydroxylase, which is essential for dopamine production. This mutation prevents NURR1 from responding to signals from the ERK1/2 pathway, a key regulator of dopamine neuron function.
- The Ser125Cys mutation impairs NURR1's ability to turn on dopamine-making genes
- This mutation blocks the effect of ERK1/2 signaling on NURR1 activity
- NURR1 function is disrupted even when dopamine signals are present
- The mutation likely reduces dopamine synthesis and increases Parkinson's risk
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 S, Kato S, Freedman LP
Nurr1 and Wnt signaling work together to control genes important for dopamine-producing brain cells. A protein called KCNIP4 acts as a brake on Wnt signaling, creating a feedback loop that helps balance Nurr1 activity, which may be relevant to brain disorders like Parkinson's.
- Nurr1 and Wnt signaling interact to regulate dopamine neuron genes
- KCNIP4 limits Wnt activity through a feedback mechanism
- This loop may help maintain balance in brain cell development
- Disruptions could affect dopamine neurons in disease
- Potential implications for Parkinson’s and related conditions
Nurr1 is phosphorylated by ERK2 in vitro and its phosphorylation upregulates tyrosine hydroxylase expression in SH-SY5Y cells.
Zhang T, Jia N, Fei E, Wang P, Liao Z, Ding L, Yan M, Nukina N, Zhou J, Wang G
Nurr1, a key protein for dopamine neuron health, is activated by being phosphorylated by ERK2, which boosts the production of tyrosine hydroxylase, a critical enzyme for dopamine synthesis. This process may help maintain dopamine levels and could be a target for therapies in NR4A2-related disorders.
- ERK2 phosphorylates Nurr1 at specific sites to boost its activity
- Phosphorylated Nurr1 increases tyrosine hydroxylase production
- This pathway may support dopamine neuron function
- Mutations in Nurr1 are linked to Parkinson’s and NR4A2-related syndromes
- Targeting this pathway could lead to new treatments
Specification of a dopaminergic phenotype from adult human mesenchymal stem cells.
Trzaska KA, Kuzhikandathil EV, Rameshwar P
Adult human bone marrow stem cells can be turned into dopamine-producing cells in just 12 days using a specific chemical cocktail. These lab-made cells show key features of early dopamine neurons, including making and releasing dopamine, but are likely immature and not fully functional yet.
- Stem cells from bone marrow become dopamine-making cells in 12 days
- Cells express key dopamine genes like Nurr1 and TH
- They release dopamine but lack mature electrical activity
- Cells are likely early-stage dopamine neuron progenitors
- Potential for future Parkinson’s cell therapy
Foxa1 and Foxa2 regulate multiple phases of midbrain dopaminergic neuron development in a dosage-dependent manner.
Ferri AL, Lin W, Mavromatakis YE, Wang JC, Sasaki H, Whitsett JA, Ang SL
Foxa1 and Foxa2 are critical transcription factors that control multiple stages of midbrain dopamine neuron development, including their formation, maturation, and function, with their effects depending on how many copies are present. These genes directly regulate Nurr1 (NR4A2), a key gene linked to NR4A2-related syndrome, suggesting they play a central role in the biological pathways affected in this condition.
- Foxa1 and Foxa2 control dopamine neuron development in the midbrain
- They regulate Nurr1 (NR4A2), a gene directly linked to NR4A2-related syndrome
- Their function depends on gene dosage—how many copies are present
- They influence both early and late stages of neuron maturation
- Findings may inform future therapies targeting NR4A2 pathways
cDNA microarray analysis of cyclosporin A (CsA)-treated human peripheral blood mononuclear cells reveal modulation of genes associated with apoptosis, cell-cycle regulation and DNA repair.
Baião AM, Wowk PF, Sandrin-Garcia P, Junta CM, Fachin AL, Mello SS, Sakamoto-Hojo ET, Donadi EA, Passos GA
Cyclosporin A alters the activity of several genes in human immune cells, including NR4A2, which is involved in cell cycle control, DNA repair, and apoptosis—processes relevant to NR4A2-related syndrome. These findings suggest that CsA may influence pathways tied to NR4A2 function, though the study does not directly examine NR4A2-related disease.
- CsA affects genes linked to DNA repair and cell cycle control
- NR4A2 is among genes modulated by CsA
- Changes in gene activity may impact immune cell function
- Findings could inform how drugs affect NR4A2 pathways
- Study uses human immune cells, not patient-derived NR4A2 models
Cross-talk between the NR3B and NR4A families of orphan nuclear receptors.
Lammi J, Rajalin AM, Huppunen J, Aarnisalo P
NR4A2 (Nurr1) and related orphan nuclear receptors can inhibit each other's activity in cells, which may affect gene regulation in ways relevant to neurological and developmental disorders. This interaction happens through their DNA-binding and dimerization regions without needing their activation domains.
- NR4A2 and NR3B receptors inhibit each other's activity
- Interaction occurs via DNA-binding and dimerization domains
- No competition for DNA or heterodimer formation involved
- Activation domains are not required for this cross-talk
- May influence gene regulation in neurodevelopmental contexts
Merging mouse transcriptome analyses with Parkinson's disease linkage studies.
Gherbassi D, Bhatt L, Thuret S, Simon HH
This study used mouse brain data to identify human genes active in dopamine-producing neurons, finding known Parkinson's genes like NR4A2 (Nurr1) and others that may be involved in Parkinson's disease. The approach helps prioritize genes in unexplained Parkinson's cases and reveals potential pathways involved in neuron health.
- Identified NR4A2 (Nurr1) as a key gene in Parkinson's disease
- Used mouse brain data to find human genes active in dopamine neurons
- Found new candidate genes linked to Parkinson's without known mutations
- May help explain how dopamine neurons fail in Parkinson's
- Provides a roadmap for finding disease-causing genes in unexplained cases
Bdnf gene is a downstream target of Nurr1 transcription factor in rat midbrain neurons in vitro.
Volpicelli F, Caiazzo M, Greco D, Consales C, Leone L, Perrone-Capano C, Colucci D'Amato L, di Porzio U
Nurr1 directly controls the BDNF gene in midbrain dopamine neurons, and low Nurr1 levels reduce BDNF and dopamine-related proteins. This suggests that boosting BDNF could help treat NR4A2-related syndrome by supporting neuron development and function.
- Nurr1 directly turns on the BDNF gene
- Low Nurr1 reduces BDNF and dopamine proteins
- BDNF supports neuron maturation and function
- Targeting BDNF may help treat NR4A2 syndrome
- Findings are from rat brain neurons, relevant to human disease
Transplantation of post-mitotic human neuroteratocarcinoma-overexpressing Nurr1 cells provides therapeutic benefits in experimental stroke: in vitro evidence of expedited neuronal differentiation and GDNF secretion.
Hara K, Matsukawa N, Yasuhara T, Xu L, Yu G, Maki M, Kawase T, Hess DC, Kim SU, Borlongan CV
Transplanting human cells engineered to overexpress Nurr1 improves recovery after stroke in rats by reducing brain damage and improving movement and behavior. These cells quickly become neurons and release a brain-protective protein, which likely explains their benefit.
- Nurr1-overexpressing cells improved stroke recovery in rats
- Cells became neurons rapidly and survived in damaged brain tissue
- They released GDNF, a protective brain protein
- Reduced brain cell loss and improved motor function
- Suggests potential for cell-based therapies in brain injury
Adult mice with reduced Nurr1 expression: an animal model for schizophrenia.
Rojas P, Joodmardi E, Hong Y, Perlmann T, Ogren SO
Mice with reduced Nurr1 levels show behaviors and brain chemistry changes linked to schizophrenia, including hyperactivity, memory issues, and altered dopamine levels in brain regions tied to the disorder. These findings suggest the model may help study the biological roots of schizophrenia, especially in relation to NR4A2/NURR1 dysfunction.
- Reduced Nurr1 causes schizophrenia-like behaviors in mice
- Dopamine imbalance in key brain areas is seen
- Effects differ between male and female mice
- Model may help study NR4A2-related brain disorders
- Findings support Nurr1's role in psychiatric conditions
Regulation of GTP cyclohydrolase I expression by orphan receptor Nurr1 in cell culture and in vivo.
Gil M, McKinney C, Lee MK, Eells JB, Phyillaier MA, Nikodem VM
Nurr1 directly controls the production of GTPCH, a key enzyme needed to make tetrahydrobiopterin (BH4), which is essential for dopamine synthesis. Without Nurr1, GTPCH levels drop, impairing dopamine production and likely contributing to the neurological symptoms seen in NR4A2-related syndrome.
- Nurr1 regulates GTPCH, a critical enzyme for dopamine production
- Low GTPCH reduces BH4, limiting dopamine synthesis
- Nurr1 loss leads to reduced GTPCH in brain cells and animal models
- This mechanism may explain dopamine deficits in NR4A2-related disorders
- Targeting GTPCH or BH4 could be a potential treatment strategy
Discovery of ligands for Nurr1 by combined use of NMR screening with different isotopic and spin-labeling strategies.
Poppe L, Harvey TS, Mohr C, Zondlo J, Tegley CM, Nuanmanee O, Cheetham J
Researchers used advanced NMR techniques to discover a small molecule that binds to Nurr1, a protein linked to NR4A2-related syndrome, with a binding strength in the low micromolar range and identified the exact site where it attaches. This finding could help develop treatments that boost Nurr1 function in people with NR4A2 mutations.
- A small molecule that binds Nurr1 was discovered
- Binding strength is in the low micromolar range
- The exact binding site on Nurr1 was identified
- Method could guide future drug development for NR4A2 syndrome
- Findings are directly relevant to NR4A2/NURR1 biology
Enhancement of dopaminergic properties and protection mediated by neuronal activation of Ras in mouse ventral mesencephalic neurones.
Chakrabarty K, Serchov T, Mann SA, Dietzel ID, Heumann R
Activating Ras in mouse brain cells boosts the development and survival of dopamine-producing neurons, which are critical for movement and often damaged in conditions like Parkinson's. This effect occurs through enhanced activity of key proteins involved in cell growth and protection, including Nurr1, a gene linked to NR4A2-related disorders.
- Activated Ras increases dopamine neuron survival and development
- Ras enhances Nurr1, a key gene in NR4A2-related syndromes
- Neurons remain electrically functional after Ras activation
- Protection against toxic stress is significantly improved
- Findings suggest potential for cell-based therapies in dopamine disorders
[Human bone marrow mesenchymal stem cells differentiated into dopaminergenic neurons in vitro].
Chai LH, Wu SX, Yan WH, Ma YF
Human bone marrow stem cells can be turned into dopamine-producing neurons in the lab using specific growth factors, and these lab-grown neurons show key signs of maturity and function, suggesting a potential source for treating Parkinson's disease and similar conditions.
- Bone marrow stem cells can become dopamine neurons in lab tests
- The process uses BDNF, forskolin, and dopamine to trigger change
- Resulting neurons produce dopamine and show mature traits
- This method may support future cell therapies for brain disorders
- Cells from patients could potentially be used for personalized treatment