Microarray analysis identifies an aberrant expression of apoptosis and DNA damage-regulatory genes in multiple sclerosis.
Satoh J, Nakanishi M, Koike F, Miyake S, Yamamoto T, Kawai M, Kikuchi S, Nomura K, Yokoyama K, Ota K, Kanda T, Fukazawa T, Yamamura T
This study finds that immune cells from people with multiple sclerosis show altered expression of genes involved in cell death and DNA repair, including increased levels of NR4A2. These findings describe a general immune system imbalance in MS rather than providing specific insights into NR4A2-related neurodevelopmental syndromes.
- NR4A2 is upregulated in T cells from multiple sclerosis patients.
- The study focuses on immune cell gene expression, not brain development.
- No clinical data or treatment implications for NR4A2 syndrome are presented.
- Findings relate to autoimmune mechanisms in MS, distinct from neurodevelopmental disorders.
In vitro and in vivo analyses of human embryonic stem cell-derived dopamine neurons.
Park CH, Minn YK, Lee JY, Choi DH, Chang MY, Shim JW, Ko JY, Koh HC, Kang MJ, Kang JS, Rhie DJ, Lee YS, Son H, Moon SY, Kim KS, Lee SH
This study shows that dopamine neurons derived from human embryonic stem cells fail to survive or maintain their identity when transplanted into rat brains. The research highlights a significant barrier in developing cell replacement therapies for Parkinson's disease using this specific method.
- Human embryonic stem cells successfully generate dopamine neurons in laboratory dishes.
- Transplanted neurons do not survive or lose their dopamine identity in rat brains.
- This approach fails to improve motor deficits in a Parkinson's disease animal model.
- The findings suggest instability of human-derived grafts in rodent environments.
Structural basis for the cell-specific activities of the NGFI-B and the Nurr1 ligand-binding domain.
Flaig R, Greschik H, Peluso-Iltis C, Moras D
This study maps the precise structural differences between the NR4A2 (Nurr1) and NGFI-B proteins that dictate how they activate genes in different cell types. It identifies specific amino acid positions and helix movements that control this activity, providing a detailed molecular blueprint of the protein's function.
- The study compares the structures of NR4A2 (Nurr1) and NGFI-B proteins.
- It reveals how small structural shifts change gene activation capabilities.
- Specific amino acid mutations alter the protein's transcriptional activity.
- This is basic molecular biology with no clinical or therapeutic implications.
The NR4A subfamily of nuclear receptors: new early genes regulated by growth factors in vascular cells.
Martínez-González J, Badimon L
This review describes how NR4A genes, including NR4A2 (Nurr1), function in blood vessels to regulate cell growth and inflammation in response to external signals. It explains that these receptors operate differently from typical nuclear receptors by not requiring a ligand to become active.
- NR4A genes act as immediate-early transcription factors in vascular cells.
- They respond to growth factors, cytokines, and lipoproteins without needing ligands.
- The paper focuses on atherosclerosis and vascular smooth muscle proliferation.
- It does not discuss neurodevelopmental phenotypes or clinical treatments for NR4A2 syndrome.
Structural variants in the retinoid receptor genes in patients with schizophrenia and other psychiatric diseases.
Feng J, Chen J, Yan J, Jones IR, Craddock N, Cook EH, Goldman D, Heston LL, Sommer SS
No strong evidence was found that structural changes in retinoid receptor genes, including NR4A2 (NURR1), contribute to schizophrenia or other psychiatric conditions in the studied patients.
- No disease-causing variants were found in NR4A2 or related retinoid genes.
- The study focused on genetic changes linked to brain development and psychiatric disorders.
- Results suggest NR4A2 structural variants are unlikely to be a major cause of schizophrenia.
- Findings do not support a significant role for these genes in the studied psychiatric conditions.
Long-term expansion of human neural progenitor cells by epigenetic stimulation in vitro.
Zhang H, Zhao Y, Zhao C, Yu S, Duan D, Xu Q
Researchers successfully expanded human neural progenitor cells in a lab dish for eight months using a new monolayer culture technique. The study confirms these cells retain their identity and can become neurons or astrocytes, offering a potential source for future dopaminergic neuron research.
- Human neural progenitor cells expand exponentially for 240 days in monolayer culture.
- Cells maintain typical progenitor markers like nestin and express Nurr1.
- The method supports ex vivo gene transfer applications.
- Findings provide a potential cell source for dopaminergic neuron development studies.
The homeodomain transcription factor Pitx3 facilitates differentiation of mouse embryonic stem cells into AHD2-expressing dopaminergic neurons.
Chung S, Hedlund E, Hwang M, Kim DW, Shin BS, Hwang DY, Kang UJ, Isacson O, Kim KS
This study shows that the transcription factor Pitx3 directs mouse stem cells to become a specific type of dopamine neuron (A9) relevant to Parkinson's disease, while Nurr1 increases the total number of dopamine neurons without changing their subtype. The research uses only mouse embryonic stem cells and does not involve human patients or NR4A2 genetics. It provides mechanistic insight into dopaminergic development but offers no direct clinical guidance for NR4A2-related syndromes.
- Pitx3 increases the proportion of A9-like dopamine neurons in mouse stem cells.
- Nurr1 increases total dopamine neuron numbers but does not change subtype proportions.
- The study uses only mouse embryonic stem cells and in vitro models.
- No human data, NR4A2 variants, or clinical trial results are included.
- Findings relate to Parkinson's disease cell therapy strategies, not NR4A2 syndrome.
Neural cell differentiation in vitro from adult human bone marrow mesenchymal stem cells.
Long X, Olszewski M, Huang W, Kletzel M
This study demonstrates that adult human bone marrow stem cells can be converted into neural-like cells in a laboratory dish using specific growth factors. The resulting cells express markers for early and mature neurons, including Nurr1 (NR4A2), as well as glial cells. This work provides no evidence regarding the treatment or management of NR4A2-related syndromes in children.
- Adult bone marrow stem cells differentiate into neural cells using specific cytokine cocktails.
- Generated cells express Nurr1 (NR4A2) alongside other neuronal and glial markers.
- The study uses only in vitro cell culture methods with no animal or human subjects.
- Findings do not address NR4A2 syndrome pathophysiology, genetics, or clinical outcomes.
Transactivation activity of Nur77 discriminates between Ca2+ and cAMP signals.
Klopotowska D, Matuszyk J, Rapak A, Gidzinska B, Cebrat M, Ziolo E, Strzadala L
This study shows that different cellular signals move the Nur77 protein to different locations within cells, with one signal keeping it in the cytoplasm and another moving it to the nucleus. This mechanism explains how cells distinguish between calcium and cAMP signals through protein location rather than just production levels. The findings are limited to basic cell biology and do not provide direct clinical insights for NR4A2-related syndromes.
- Nur77 protein moves to the nucleus with cAMP signals but stays in the cytoplasm with calcium signals.
- Both signals increase gene transcription, but only cAMP strongly activates Nur77's transactivation function.
- The study uses PC12 cells, a standard laboratory cell line for neuroendocrine research.
- Results suggest protein location, not just amount, determines how Nur77 responds to cellular signals.
Nurr1 co-localizes with EphB1 receptors in the developing ventral midbrain, and its expression is enhanced by the EphB1 ligand, ephrinB2.
Calò L, Spillantini M, Nicoletti F, Allen ND
This study shows that the EphB1 receptor and its ligand ephrinB2 regulate Nurr1 expression in developing mouse brains, suggesting a mechanism for dopaminergic neuron development. The findings are based entirely on embryonic mouse tissue and do not involve human patients or clinical treatments.
- EphB1 receptors and Nurr1 share similar expression patterns in early mouse embryonic midbrain.
- Applying ephrinB2 ligand increases Nurr1 mRNA and protein levels in mouse brain explants.
- High concentrations of ephrinB2 do not affect Nurr1 expression, indicating a dose-dependent effect.
- The study suggests EphB1 activation helps dopaminergic neurons develop in mice.
- No human data, clinical trials, or direct therapeutic implications are presented.
The NGFI-B family of transcription factors regulates expression of 3beta-hydroxysteroid dehydrogenase type 2 in the human ovary.
Havelock JC, Smith AL, Seely JB, Dooley CA, Rodgers RJ, Rainey WE, Carr BR
The NGFI-B protein, also known as NR4A1, helps control the production of progesterone in human ovarian cells by turning on the HSD3B2 gene, which is essential for hormone synthesis during ovulation.
- NGFI-B boosts HSD3B2 gene activity in ovarian cells
- This increases progesterone production during ovulation
- NR4A1 (NGFI-B) is more active than NURR1 or NOR-1 in human ovaries
- HSD3B2 activation depends on a specific NGFI-B binding site
- Hormones and signals like FSH trigger NGFI-B expression
Induction patterns of transcription factors of the nur family (nurr1, nur77, and nor-1) by typical and atypical antipsychotics in the mouse brain: implication for their mechanism of action.
Maheux J, Ethier I, Rouillard C, Lévesque D
This study measures how different antipsychotic drugs change the levels of NR4A2 (Nurr1) and related genes in mouse brains. It finds that these drugs alter gene expression patterns in dopamine-related brain regions, which helps distinguish between typical and atypical medications.
- Researchers measured NR4A2 gene activity in mouse brains after giving antipsychotic drugs.
- Typical and atypical antipsychotics create distinct patterns of NR4A2 family gene expression.
- Drug effects on these genes correlate with dopamine receptor binding in the striatum.
- The study uses mice, not humans, to observe these molecular changes.
Protein-protein interactions and transcriptional antagonism between the subfamily of NGFI-B/Nur77 orphan nuclear receptors and glucocorticoid receptor.
Martens C, Bilodeau S, Maira M, Gauthier Y, Drouin J
This study defines a molecular mechanism where glucocorticoids suppress gene expression by physically interacting with NR4A2 family proteins. It demonstrates that the glucocorticoid receptor directly binds to these orphan nuclear receptors to block their ability to activate transcription.
- Glucocorticoids repress genes targeted by NGFI-B, Nurr1, and NOR1.
- The glucocorticoid receptor physically interacts with all three NR4A2 family members.
- This interaction occurs via the DNA binding domains of the proteins.
- The mechanism resembles known transrepression pathways involving other transcription factors.
Dopaminergic neurons.
Chinta SJ, Andersen JK
This article explains that Nurr1 is a key transcription factor required for the development of dopaminergic neurons, which are the brain cells lost in Parkinson's disease. It highlights that while these neurons control movement and mood, their exact cause of death remains unknown.
- Nurr1 helps build midbrain dopamine neurons essential for movement and behavior.
- Loss of these neurons causes Parkinson's disease symptoms.
- The specific reason these neurons die is still unknown.
Presynaptic dopaminergic properties of differentiated mouse embryonic stem cells.
Nakano Y, Hirko AC, Smith AD, Oka M, Dawson R, Peris J, Terada N, Meyer EM
Differentiated mouse embryonic stem cells develop presynaptic dopaminergic functions, including dopamine uptake and release, when co-cultured with PA6 support cells. These cells express key dopaminergic genes such as Nurr1, TH, VMAT2, and DAT, demonstrating their potential for maintaining dopaminergic homeostasis in vitro.
- Mouse embryonic stem cells differentiate into dopaminergic neurons with functional presynaptic properties.
- Co-culture with PA6 cells yields approximately 30% tyrosine hydroxylase-positive cells.
- Cells exhibit sodium-dependent dopamine uptake and calcium-dependent dopamine release.
- Key dopaminergic genes including Nurr1, VMAT2, and DAT are expressed in these cultures.
Nurr1 mutational screen in Parkinson's disease.
Tan EK, Chung H, Chandran VR, Tan C, Shen H, Yew K, Pavanni R, Puvan KA, Wong MC, Teoh ML, Yih Y, Zhao Y
No pathogenic mutations in the Nurr1 gene were found in Asian patients with familial or young-onset Parkinson's disease. The intron 7 +33 C-->T variant is common in Malay and Indian populations and is a harmless genetic variation, not a disease-causing mutation.
- No harmful Nurr1 mutations found in Asian Parkinson's patients
- Intron 7 +33 C-->T is a common variant in some ethnic groups
- This variant is not linked to Parkinson's disease
- It is a harmless genetic difference, not a disease cause
Chronic lithium decreases Nurr1 expression in the rat brain and impairs spatial discrimination.
Al Banchaabouchi M, Peña de Ortíz S, Menéndez R, Ren K, Maldonado-Vlaar CS
Chronic lithium treatment reduces Nurr1 levels in the rat hippocampus and impairs spatial learning. This study links lithium-induced cognitive deficits to decreased expression of the NR4A2 protein in specific brain regions.
- Lithium lowers Nurr1 expression in rat hippocampal regions like CA1.
- Rats given lithium show impaired spatial discrimination learning.
- Nurr1 levels rise back to normal after spatial training in treated rats.
- The study uses a rat model, not human participants or clinical data.
Nur77 family of nuclear hormone receptors.
Hsu HC, Zhou T, Mountz JD
This review describes the general biological functions of the Nur77 family of proteins, including Nurr1 (NR4A2), in cell growth, immune response, and inflammation. It highlights their dual roles in the nucleus and mitochondria but does not provide specific insights into NR4A2-related syndromes or potential treatments for affected children.
- Nurr1 is part of the Nur77 family of orphan nuclear receptors involved in transcription regulation.
- These proteins influence cell death, growth, and immune function in various tissues.
- The review focuses on general biochemical mechanisms rather than specific disease pathways.
- No clinical data or treatment strategies for NR4A2-related conditions are presented.
NGFI-B (Nurr77/Nr4a1) orphan nuclear receptor in rat pinealocytes: circadian expression involves an adrenergic-cyclic AMP mechanism.
Humphries A, Weller J, Klein D, Baler R, Carter DA
This study maps the daily biological clock in rat pineal glands, showing that NGFI-B (Nur77/Nr4a1) protein levels rise at night through adrenergic signaling. It identifies Fra-2 as a regulatory partner for this specific receptor within the pineal gland.
- NGFI-B mRNA and protein peak at night in rat pinealocytes.
- Adrenergic receptors and cyclic AMP drive this nocturnal increase.
- Fra-2 protein regulates NGFI-B expression in the pineal gland.
- The study focuses on circadian rhythms, not NR4A2 or Nurr1.
The orphan nuclear receptors NURR1 and NGFI-B modulate aromatase gene expression in ovarian granulosa cells: a possible mechanism for repression of aromatase expression upon luteinizing hormone surge.
Wu Y, Ghosh S, Nishi Y, Yanase T, Nawata H, Hu Y
This study shows that NURR1 and NGFI-B proteins repress aromatase gene expression in ovarian cells, a mechanism relevant to reproductive biology rather than neurodevelopment. The findings do not provide direct insight into NR4A2-related syndrome or potential treatments for the child's condition. This research focuses on hormonal regulation in the ovary, which is unrelated to the dopaminergic pathways affected by NR4A2 mutations.
- NURR1 and NGFI-B repress aromatase gene expression in human ovarian granulosa cells.
- This repression occurs rapidly after luteinizing hormone surge during follicular development.
- The study uses a human granulosa-like tumor cell line (KGN) for analysis.
- DNA-binding domain of NURR1 is required for this transcriptional repression.
- Findings relate to ovarian steroidogenesis, not central nervous system function.
Nuclear orphan receptor Nurr1 directly transactivates the osteocalcin gene in osteoblasts.
Pirih FQ, Tang A, Ozkurt IC, Nervina JM, Tetradis S
This study shows that Nurr1 regulates bone formation by directly activating the osteocalcin gene in bone cells. It does not address brain development, dopamine signaling, or neurological symptoms relevant to NR4A2 syndrome.
- Nurr1 activates osteocalcin expression in bone-forming cells.
- The mechanism involves direct binding to specific DNA sites in the osteocalcin promoter.
- This research focuses entirely on skeletal biology, not neurology.
- No findings relate to dopaminergic neurons or human NR4A2 phenotypes.
Expression, purification, and initial structural characterization of rat orphan nuclear receptor NOR-1 LBD domain.
Razzera G, Vernal J, Portugal RV, Calgaro MR, Fernandez P, Zakin MM, Polikarpov I, Terenzi H
Researchers determined the physical structure of a specific part of the NOR-1 protein, which is closely related to NR4A2. This work provides structural data for laboratory analysis but does not offer clinical insights or treatment options for patients.
- The study characterizes the rat NOR-1 protein domain in a lab setting.
- NOR-1 belongs to the same family as NR4A2 (Nurr1).
- No ligands or binding sites are identified for this receptor.
- The findings apply only to basic molecular biology research.
Tyrosine hydroxylase-positive neurons intrinsic to the human striatum express the transcription factor Nurr1.
Cossette M, Parent A, Lévesque D
This study confirms that a small population of dopamine-producing neurons exists naturally within the human striatum and shares key molecular features with those in the substantia nigra. It establishes that these intrinsic striatal neurons consistently express both tyrosine hydroxylase and the transcription factor Nurr1.
- Dopamine neurons exist intrinsically within the human striatum, not just in the substantia nigra.
- These striatal neurons express Nurr1, the same transcription factor linked to NR4A2-related syndromes.
- The study uses post-mortem tissue from seven healthy individuals to reach these conclusions.
- Findings describe basic neuroanatomy without testing treatments or analyzing patient genetics.
Identification of a novel co-regulator interaction surface on the ligand binding domain of Nurr1 using NMR footprinting.
Codina A, Benoit G, Gooch JT, Neuhaus D, Perlmann T, Schwabe JW
Researchers identify a specific surface on the Nurr1 protein where co-repressor molecules bind to regulate gene activity. This discovery clarifies how Nurr1 functions at a molecular level by revealing an interaction site distinct from the classical ligand-binding groove.
- Nurr1 lacks a traditional ligand binding cavity filled with hydrophobic side chains.
- Co-repressors SMRT and NCoR bind to a novel hydrophobic patch on Nurr1.
- This interaction occurs in a groove between helices 11 and 12 of the protein.
- Mutations at this site abolish Nurr1 activation, confirming its functional importance.
Angiotensin II early regulated genes in H295R human adrenocortical cells.
Romero DG, Plonczynski M, Vergara GR, Gomez-Sanchez EP, Gomez-Sanchez CE
This study identifies 11 genes rapidly turned on by angiotensin II in human adrenal cells, including Nurr1 (NR4A2), which is involved in hormone production and cellular stress responses. These genes are activated before aldosterone is made and may help explain how angiotensin II drives adrenal hormone release.
- Angiotensin II quickly turns on 11 genes in adrenal cells
- NR4A2 (Nurr1) is among the genes activated
- Gene activation happens before aldosterone is produced
- Other hormones like potassium and endothelin also trigger these genes
- These genes may control how the adrenal gland responds to stress
Differentiation and transcription factor gene therapy in experimental parkinson's disease: sonic hedgehog and Gli-1, but not Nurr-1, protect nigrostriatal cell bodies from 6-OHDA-induced neurodegeneration.
Hurtado-Lorenzo A, Millan E, Gonzalez-Nicolini V, Suwelack D, Castro MG, Lowenstein PR
This study shows that gene therapy using Sonic hedgehog or Gli-1 protects dopaminergic neurons in rats from toxin-induced death, while Nurr-1 (NR4A2) provides no protection. The findings suggest that NR4A2 is not a viable target for neuroprotective gene therapy in this context.
- Sonic hedgehog and Gli-1 protect dopaminergic cell bodies in rat brains from neurotoxin damage.
- NR4A2 (Nurr-1) gene therapy fails to protect neurons or axons in this Parkinson's model.
- The study uses a rat model, not human patients or clinical trials.
- Results indicate NR4A2 is ineffective for neuroprotection against 6-OHDA-induced degeneration.
Nurr1, an orphan nuclear receptor with essential functions in developing dopamine cells.
Perlmann T, Wallén-Mackenzie A
Nurr1 is a transcription factor essential for the development and survival of dopamine neurons in the brain. It functions by partnering with another protein, RXR, to activate genes required for dopamine production and neuronal health.
- Nurr1 drives dopamine neuron development in the embryonic midbrain.
- It partners with RXR to promote dopamine neuron survival.
- RXR ligands support neurons through this Nurr1-RXR partnership.
- Nurr1 maintains adult dopamine neurons and regulates other genes.
Assessment of Nurr1 nucleotide variations in familial Parkinson's disease.
Levecque C, Destée A, Mouroux V, Amouyel P, Chartier-Harlin MC
This study found no evidence that mutations in the NR4A2 gene (Nurr1) contribute to familial Parkinson's disease in a French population, suggesting it is unlikely to be a major cause in this group.
- No NR4A2 mutations were found in French familial Parkinson's cases
- Previous links between NR4A2 and Parkinson's were not confirmed
- NR4A2 is unlikely to be a major cause of familial Parkinson's in this population
NR4A2 and schizophrenia: lack of association in a Portuguese/Brazilian study.
Ruano D, Macedo A, Dourado A, Soares MJ, Valente J, Coelho I, Santos V, Azevedo MH, Goodman A, Hutz MH, Gama C, Lobato MI, Belmonte-de-Abreu P, Palha JA
This study finds no evidence that the specific NR4A2 mutations previously linked to schizophrenia are present in a cohort of Portuguese and Brazilian patients with the condition. The results suggest these particular genetic variants do not contribute to schizophrenia in this population, though they do not rule out other potential roles for NR4A2 in brain development.
- Researchers screened 258 schizophrenia patients for known NR4A2 mutations.
- None of the previously reported schizophrenia-linked mutations were found.
- The study confirms these specific variants are not associated with schizophrenia in this group.
- Altered NR4A2 expression or other mutations may still play a role in the disease.
Efficient induction of dopaminergic neurons from embryonic stem cells for application to Parkinson's disease.
Kim DW
This study demonstrates that overexpressing the Nurr1 protein in embryonic stem cells significantly increases the efficiency of generating dopamine-producing neurons. The modified cells mature into functional dopaminergic neurons and show improved survival and phenotype after transplantation in animal models.
- Nurr1 overexpression boosts dopaminergic neuron generation from stem cells to nearly 90% efficiency.
- Genetically modified cells produce higher levels of dopamine than unmodified controls.
- Transplanted cells maintain dopaminergic characteristics in living animal models.
- The method combines genetic engineering with specific culture conditions for cell therapy.
Absence of NR4A2 exon 1 mutations in 108 families with autosomal dominant Parkinson disease.
Ibáñez P, Lohmann E, Pollak P, Durif F, Tranchant C, Agid Y, Dürr A, Brice A, French Parkinson's Disease Genetics Study Group
This study found no mutations in NR4A2 exon 1 among 108 families with autosomal dominant Parkinson’s disease, suggesting that NR4A2 exon 1 is not a common cause of inherited Parkinson’s in this group.
- NR4A2 exon 1 mutations were not found in 108 Parkinson’s families
- NR4A2 exon 1 is unlikely a major cause of inherited Parkinson’s
- Results help rule out a specific genetic cause in some cases
Evaluation of the role of Nurr1 in a large sample of familial Parkinson's disease.
Nichols WC, Uniacke SK, Pankratz N, Reed T, Simon DK, Halter C, Rudolph A, Shults CW, Conneally PM, Foroud T, Parkinson Study Group
Genetic changes in the Nurr1 gene are not linked to Parkinson's disease in this large group of families with the condition, suggesting Nurr1 is unlikely to be a major cause of familial Parkinson's in this population.
- No link found between Nurr1 gene changes and Parkinson's in 783 patients
- The previously reported Nurr1 mutations were not found in this study
- Nurr1 is not a significant risk factor for familial Parkinson's here
- Results suggest other genes likely play bigger roles in this group
Novel splicing variant of the human orphan nuclear receptor Nurr1 gene.
Xu PY, Le WD
Researchers identified a new version of the Nurr1 gene that is present in body tissues like blood and liver but absent from the brain. This specific variant shows reduced activity in laboratory tests, suggesting it functions differently than the standard gene.
- The novel Nurr1 variant exists in non-neuronal human tissues such as lymphocytes and liver.
- The variant is not found in the adult brain or spinal cord.
- Laboratory assays show this variant has significantly lower transcriptional activity.
- The study does not link this variant to clinical symptoms or disease.