Neuronal development genes are key elements mediating the reinforcing effects of methamphetamine, amphetamine, and methylphenidate.
Dela Peña I, Jeon SJ, Lee E, Ryu JH, Shin CY, Noh M, Cheong JH
This study identifies NR4A2 as one of several brain development genes that change expression in rat brains after exposure to psychostimulants like methamphetamine. The research focuses on addiction mechanisms and drug reinforcement rather than the developmental or neurological aspects of NR4A2-related syndrome.
- NR4A2 upregulation occurs in rat striatum following stimulant pretreatment.
- Study links brain development genes to psychostimulant addiction susceptibility.
- Research uses animal models of drug self-administration and place preference.
- Findings relate to addiction biology, not NR4A2 syndrome pathophysiology.
Short-term atrazine exposure causes behavioral deficits and disrupts monoaminergic systems in male C57BL/6 mice.
Lin Z, Dodd CA, Filipov NM
Short-term exposure to the herbicide atrazine disrupts dopamine and serotonin systems in mice, leading to behavioral changes like reduced movement, memory problems, and increased anxiety-like behavior, even at relatively low doses.
- Atrazine harms brain chemistry linked to dopamine and serotonin
- Mice showed memory and movement issues after exposure
- Behavioral changes appeared at doses as low as 25 mg/kg
- Striatal dopamine and serotonin metabolites increased
- No change in key dopamine-related gene or protein levels
A novel strategy to increase the proliferative potential of adult human β-cells while maintaining their differentiated phenotype.
Aly H, Rohatgi N, Marshall CA, Grossenheider TC, Miyoshi H, Stappenbeck TS, Matkovich SJ, McDaniel ML
This study uses human pancreatic beta cells to explore methods for increasing cell proliferation while maintaining their function. It identifies specific signaling pathways that boost replication but does not involve NR4A2, dopaminergic neurons, or Parkinson's disease mechanisms.
- Research focuses on human pancreatic beta cells and insulin secretion.
- NR4A2 appears only as a marker of beta-cell identity, not the study target.
- No connection to NR4A2-related syndromes or dopaminergic neuron biology.
- Findings are preclinical and unrelated to current therapeutic strategies for this syndrome.
Character comparison of abdomen-derived and eyelid-derived mesenchymal stem cells.
Kim SH, Bang SH, Park SA, Kang SY, Park KD, Oh IU, Yoo SH, Kim H, Kim CH, Baek SY
Abdomen-derived and eyelid-derived stem cells have different characteristics despite coming from similar fat tissues, with eyelid cells showing higher levels of genes linked to nerve cells and cartilage. These differences may affect which type of stem cell is best suited for specific medical treatments.
- Eyelid stem cells differ in shape and gene expression from belly fat stem cells
- Eyelid cells show higher levels of nerve and cartilage-related genes
- Both cell types can become multiple cell types and remain genetically stable
- Differences may influence treatment choices in regenerative medicine
Late maternal hypothyroidism alters the expression of Camk4 in neocortical subplate neurons: a comparison with Nurr1 labeling.
Navarro D, Alvarado M, Morte B, Berbel D, Sesma J, Pacheco P, Morreale de Escobar G, Bernal J, Berbel P
Maternal hypothyroidism delays the normal shutdown of specific brain development markers in offspring, potentially altering cortical connectivity. This study links thyroid hormone levels to the timing of gene expression in neocortical neurons during late gestation and early postnatal life.
- Maternal hypothyroidism delays Camk4 protein extinction in subplate neurons by one to two days.
- Prolonged Camk4 and Nurr1 expression may disrupt normal cortical connectivity patterns.
- The study uses a mouse model of prematurity to simulate maternal thyroid hormone deprivation.
- Findings suggest thyroid hormones regulate the timing of neocortical developmental milestones.
New insights into FoxE1 functions: identification of direct FoxE1 targets in thyroid cells.
Fernández LP, López-Márquez A, Martínez AM, Gómez-López G, Santisteban P
FoxE1 regulates key thyroid genes, including Nis and Duox2, which are essential for thyroid hormone production. This study identifies new direct targets of FoxE1, revealing its broad role in maintaining thyroid function.
- FoxE1 directly controls Nis and Duox2 genes in thyroid cells
- FoxE1 works with NF1/CTF to activate thyroid gene promoters
- Silencing FoxE1 affects multiple genes involved in thyroid function
- Findings help explain how thyroid development and hormone production are regulated
Three-dimensional neural differentiation of embryonic stem cells with ACM induction in microfibrous matrices in bioreactors.
Liu N, Ouyang A, Li Y, Yang ST
This study demonstrates a scalable method for producing neural cells from embryonic stem cells using 3D microfibrous matrices and conditioned medium. The process yields a higher percentage of neural progenitor cells compared to traditional 2D methods, with increased expression of key neural markers including Nurr1.
- The study uses murine embryonic stem cells, not human patient cells or clinical data.
- It focuses on manufacturing efficiency for mass-producing neural cells in bioreactors.
- Nurr1 is mentioned only as a marker gene upregulated during differentiation.
- No treatment, therapy, or clinical outcome for NR4A2-related syndromes is tested.
Rotenone could activate microglia through NFκB associated pathway.
Yuan YH, Sun JD, Wu MM, Hu JF, Peng SY, Chen NH
Rotenone, a pesticide linked to Parkinson's disease risk, triggers inflammation in immune brain cells by activating the NFκB pathway and reducing Nurr1 protein levels. This study demonstrates a mechanism for environmental toxicity but does not involve human patients or NR4A2-specific therapies.
- Rotenone activates microglia via the NFκB signaling pathway in cell and animal models.
- The pesticide increases pro-inflammatory cytokines TNFα and IL-1β in brain tissue.
- Rotenone reduces nuclear Nurr1 protein levels, linking environmental exposure to molecular changes.
- This is preclinical research with no direct clinical application for NR4A2 syndrome patients.
Intracranial self-stimulation facilitates active-avoidance retention and induces expression of c-Fos and Nurr1 in rat brain memory systems.
Aldavert-Vera L, Huguet G, Costa-Miserachs D, Ortiz SP, Kádár E, Morgado-Bernal I, Segura-Torres P
This study shows that electrical stimulation of reward centers in rat brains improves memory retention and increases Nurr1 protein levels in specific brain regions. The findings demonstrate a link between behavioral learning, neural activation markers, and Nurr1 expression in animal models.
- ICSS improved memory retention in rats performing active-avoidance tasks.
- Nurr1 expression increased in the amygdala following conditioning.
- c-Fos and Nurr1 levels rose transiently after stimulation in multiple brain areas.
- Combined learning and stimulation had additive effects on c-Fos in the CA3 region.
[Effects of DAPT on proliferation of human dental pulp cells and Notch signaling pathway].
Zou XY, Zhuang H, Yue L, Gao XJ
DAPT, a drug that blocks the Notch signaling pathway, reduces the activity of this pathway in human dental pulp cells and slows their growth. The gene NR4A2, which is part of this pathway, is also downregulated by DAPT.
- DAPT blocks Notch signaling in human dental pulp cells
- NR4A2 gene expression decreases with DAPT treatment
- Cell growth slows significantly after DAPT exposure
- DAPT affects the normal life cycle of these cells
HDAC3 is a negative regulator of cocaine-context-associated memory formation.
Rogge GA, Singh H, Dang R, Wood MA
HDAC3 suppresses the formation of cocaine-context memories in mice by limiting gene expression in the nucleus accumbens. Reducing HDAC3 leads to stronger memory formation and increased activity of genes like NR4A2, which are linked to brain plasticity and behavior.
- HDAC3 blocks cocaine-related memory formation
- Lower HDAC3 increases NR4A2 and c-Fos gene activity
- HDAC3 loss boosts memory strength in mice
- Changes in histone acetylation affect gene expression
- Findings may inform treatments for addiction-related behaviors
Early life permethrin exposure induces long-term brain changes in Nurr1, NF-kB and Nrf-2.
Carloni M, Nasuti C, Fedeli D, Montani M, Vadhana MS, Amici A, Gabbianelli R
Early exposure to the common pesticide permethrin causes lasting changes in brain signaling pathways related to dopamine and inflammation in rats. These findings suggest that environmental toxins may contribute to long-term neurological risks by altering genes like Nurr1 during critical developmental windows.
- Permethrin exposure in young rats alters Nurr1 gene expression in the striatum, hippocampus, and cerebellum.
- The study links early pesticide exposure to long-term dopaminergic neuronal disorders via Nurr1 changes.
- Inflammatory markers NF-kB and Nrf-2 show persistent alterations after neonatal permethrin treatment.
- Effects persist into adulthood, indicating potential long-term brain aging processes.
Chronic co-administration of nicotine and methamphetamine causes differential expression of immediate early genes in the dorsal striatum and nucleus accumbens of rats.
Saint-Preux F, Bores LR, Tulloch I, Ladenheim B, Kim R, Thanos PK, Volkow ND, Cadet JL
Chronic nicotine and methamphetamine exposure alters the expression of immediate early genes, including NR4A2, in specific brain regions of rats. These molecular changes differ when the drugs are used together compared to individually, suggesting complex interactions in reward pathways.
- NR4A2 expression increases in the striatum after nicotine or methamphetamine exposure.
- Drug combinations cause distinct gene expression patterns compared to single drugs.
- Study uses rat models of addiction, not human patients with NR4A2 syndromes.
- Findings relate to general neuroplasticity rather than specific NR4A2-related developmental disorders.
Morphine administration modulates expression of Argonaute 2 and dopamine-related transcription factors involved in midbrain dopaminergic neurons function.
García-Pérez D, Sáez-Belmonte F, Laorden ML, Núñez C, Milanés MV
This study shows that morphine exposure and withdrawal alter the levels of Nurr1, a transcription factor also known as NR4A2, in rat brain regions involved in dopamine regulation. The findings suggest that changes in Nurr1 expression are linked to shifts in dopamine activity during opioid use and withdrawal.
- Acute morphine increases Nurr1 and Pitx3 expression in the rat ventral tegmental area.
- Morphine withdrawal decreases Ago2 but maintains or increases Nurr1 levels in rats.
- These molecular changes correlate with altered dopamine turnover in the nucleus accumbens.
- The study uses rat models to explore mechanisms of addiction and dopamine regulation.
Altered gene expression in the dorsolateral prefrontal cortex of individuals with schizophrenia.
Guillozet-Bongaarts AL, Hyde TM, Dalley RA, Hawrylycz MJ, Henry A, Hof PR, Hohmann J, Jones AR, Kuan CL, Royall J, Shen E, Swanson B, Zeng H, Kleinman JE
This study finds that the NR4A2 gene shows altered expression levels in the brains of individuals with schizophrenia, but it does not investigate NR4A2-related syndrome or offer any clinical insights for affected children. The research focuses on general schizophrenia pathology rather than specific genetic variants relevant to this family.
- NR4A2 expression differs in the prefrontal cortex of people with schizophrenia.
- The study analyzes brain tissue from 19 patients and 33 controls.
- Findings are limited to Brodmann area 9, not broader NR4A2 syndrome pathology.
- No treatment or clinical guidance for NR4A2-related conditions is provided.
Nuclear receptor NR4A2 orchestrates Th17 cell-mediated autoimmune inflammation via IL-21 signalling.
Raveney BJ, Oki S, Yamamura T
This study shows that NR4A2 drives autoimmune inflammation by regulating T cells that produce IL-21 and IL-17. Blocking NR4A2 prevents these immune cells from maturing and protects mice from autoimmune disease symptoms.
- NR4A2 is essential for Th17 cell differentiation and function in autoimmune models.
- Blocking NR4A2 stops IL-21 production and reduces inflammatory T cell activity.
- The findings apply to immune system regulation, not dopaminergic neuron development.
- This research focuses on autoimmunity rather than NR4A2-related movement disorders.
Systemic administration of valproic acid and zonisamide promotes differentiation of induced pluripotent stem cell-derived dopaminergic neurons.
Yoshikawa T, Samata B, Ogura A, Miyamoto S, Takahashi J
This study shows that valproic acid and zonisamide improve the survival and differentiation of dopaminergic neurons derived from stem cells in rat models. The findings suggest these drugs could potentially enhance cell replacement therapies for Parkinson's disease by supporting neuron growth in the host brain.
- Valproic acid and zonisamide increased dopaminergic neuron markers in stem cell cultures.
- Systemic drug administration improved neuron survival in transplanted rat brains.
- The study focuses on Parkinson's disease cell therapy, not NR4A2 syndrome treatment.
- Results are preclinical and do not involve human patients or NR4A2 variants.
An intra-articular salmon calcitonin-based nanocomplex reduces experimental inflammatory arthritis.
Ryan SM, McMorrow J, Umerska A, Patel HB, Kornerup KN, Tajber L, Murphy EP, Perretti M, Corrigan OI, Brayden DJ
This study shows that a nanocomplex combining salmon calcitonin and hyaluronic acid reduces joint inflammation and preserves bone structure in mice with induced arthritis. The treatment works by lowering the expression of NR4A2 and other inflammatory markers in cells.
- Nanocomplexes reduce NR4A2 mRNA expression in human cell lines.
- Intra-articular injection reduces inflammation in mouse arthritis models.
- Local bone architecture is preserved during treatment in mice.
- The study uses preclinical animal and cell models only.
Human Stem Cell Derivatives Retain More Open Epigenomic Landscape When Derived from Pluripotent Cells than from Tissues.
Parsons XH
This study compares the epigenetic landscapes of stem cells derived from human embryonic stem cells versus adult brain tissue to understand their regenerative potential. It finds that pluripotent-derived cells maintain a more open chromatin structure, which correlates with greater developmental plasticity compared to tissue-derived cells.
- Pluripotent-derived neuronal progenitors retain an open epigenomic landscape.
- Tissue-derived neural stem cells show increased chromatin silencing via H3K9 methylation.
- Open chromatin correlates with higher intrinsic plasticity and regenerative potential.
- The study profiles global chromatin changes during lineage restriction.
PIASγ enhanced SUMO-2 modification of Nurr1 activation-function-1 domain limits Nurr1 transcriptional synergy.
Arredondo C, Orellana M, Vecchiola A, Pereira LA, Galdames L, Andrés ME
This study identifies a specific molecular mechanism where the protein PIASγ limits Nurr1 activity by attaching SUMO-2 to it, thereby reducing its ability to activate genes. It also shows that PIASγ can repress Nurr1 through direct physical interaction independent of this modification process. These findings clarify how Nurr1 function is regulated at a cellular level but do not offer immediate clinical insights or treatments for NR4A2-related syndromes.
- PIASγ attaches SUMO-2 to Nurr1 at lysine 91, reducing its gene activation power.
- This modification specifically limits Nurr1's ability to work synergistically on complex promoters.
- PIASγ also represses Nurr1 through direct binding, regardless of its enzyme activity.
- The research focuses on basic molecular interactions without human or animal disease models.
Parkinson's disease in the nuclear age of neuroinflammation.
Nolan YM, Sullivan AM, Toulouse A
This review discusses how nuclear receptors, including Nurr1, regulate neuroinflammation and dopaminergic neuron degeneration in Parkinson's disease. It highlights these receptors as potential therapeutic targets for treating the condition.
- Nuclear receptors control inflammation linked to Parkinson's disease progression.
- Nurr1 helps regulate the survival of dopamine-producing neurons.
- The paper reviews Nurr1, PPARs, and other receptors as drug targets.
- Transcriptional control is key to preventing neurodegeneration in this context.
LMX1B is part of a transcriptional complex with PSPC1 and PSF.
Hoekstra EJ, Mesman S, de Munnik WA, Smidt MP
This study identifies physical interactions between the transcription factor LMX1B and proteins PSPC1, PSF, GRLF1, DHX9, MYO1C, HSP70, and TMPO in dopaminergic cells. It suggests these interactions help regulate Nurr1 target genes and may influence neurite outgrowth during brain development.
- LMX1B binds to PSPC1 and PSF within a larger protein complex.
- The study links LMX1B to the regulation of Nurr1 target genes.
- Several interactors, including GRLF1 and MYO1C, are associated with neurite outgrowth.
- This is preclinical molecular biology research using cell lines and animal models.
- No human clinical data or direct relevance to NR4A2 variants is presented.
Neurochemical profiling of dopaminergic neurons in the forebrain of a cichlid fish, Astatotilapia burtoni.
O'Connell LA, Fontenot MR, Hofmann HA
This study compares gene expression in fish brains to understand how dopamine systems evolved across species. It confirms that specific genes controlling dopamine neuron development are conserved between cichlid fish and mammals.
- The research focuses on evolutionary conservation of dopamine pathways in fish, not human disease.
- It analyzes gene expression patterns in adult fish brains to map neural structures.
- No clinical data, patient cohorts, or potential treatments for NR4A2-related syndromes are presented.
- Findings describe basic biology and do not offer actionable insights for patient care.
Nuclear import and export signals control the subcellular localization of Nurr1 protein in response to oxidative stress.
García-Yagüe ÁJ, Rada P, Rojo AI, Lastres-Becker I, Cuadrado A
Oxidative stress pushes the Nurr1 protein out of the cell nucleus and into the cytoplasm, where it cannot regulate genes. This movement is controlled by specific import and export signals on the protein itself.
- Nurr1 shuttles between the nucleus and cytoplasm using specific signal sequences.
- Oxidative stress causes Nurr1 to exit the nucleus and accumulate in the cytoplasm.
- Antioxidants can reverse this stress-induced export of Nurr1 from the nucleus.
- Loss of nuclear Nurr1 leads to reduced expression of its target genes.
Analysis of PITX3 gene in patients with multisystem atrophy, progressive supranuclear palsy and corticobasal degeneration.
Jamrozik Z, Berdynski M, Zekanowski C, Baranczyk-Kuzma A, Sławek J, Kuzma-Kozakiewicz M, Maruszak A, Kwiecinski H
No disease-causing mutations in the PITX3 gene were found in people with multisystem atrophy, progressive supranuclear palsy, or corticobasal degeneration. This suggests PITX3 is unlikely to be a major genetic cause of these conditions.
- No harmful PITX3 mutations found in MSA, PSP, or CBD patients
- PITX3 not a major cause of these neurodegenerative disorders
- Nurr1, Pitx3, and EN1 are important for dopamine neuron health
- Study focused on human clinical cases with detailed diagnoses
Pituitary adenylyl cyclase-activating polypeptide receptor re-sensitization induces plastic changes in the dopaminergic phenotype in the mature avian retina.
Fleming RL, Silveira MS, Santos LE, Henze IP, Gardino PF, de Mello MC, de Mello FG
Blocking PACAP signaling in mature chick retinas increases the number of cells expressing tyrosine hydroxylase, a key enzyme for dopamine production. This suggests that NURR1-positive cells in the retina can be induced to adopt a dopaminergic phenotype when specific receptor pathways are modulated.
- PACAP antagonist treatment increases tyrosine hydroxylase positive cells in mature avian retinas.
- NURR1 is present in mature chick retina, exceeding the number of dopamine-producing cells.
- Blocking PACAP signaling induces plastic changes toward a dopaminergic phenotype.
- Study uses chick embryos and adult birds, not human subjects or mammalian models.
Nato3 integrates with the Shh-Foxa2 transcriptional network regulating the differentiation of midbrain dopaminergic neurons.
Nissim-Eliraz E, Zisman S, Schatz O, Ben-Arie N
This study identifies Nato3 as a new component of the genetic network that guides midbrain dopamine neuron development, showing it is controlled by Shh signaling and regulates Nurr1 expression. The findings provide mechanistic insights into how these neurons form but do not offer direct clinical information or treatment options for NR4A2-related syndromes.
- Nato3 expression increases as midbrain dopamine neurons differentiate in cell cultures.
- The transcription factor Foxa2 directly controls Nato3 gene activity.
- Blocking Shh signaling reduces Nato3 levels, linking it to early brain patterning.
- Nato3 forms a feedback loop with Shh and Foxa2 pathways.
- Nato3 influences Nurr1 transcription but does not affect TH expression.
Restriction of neural precursor ability to respond to Nurr1 by early regional specification.
Soldati C, Cacci E, Biagioni S, Carucci N, Lupo G, Perrone-Capano C, Saggio I, Augusti-Tocco G
Forced expression of Nurr1 only directs neural precursor cells to become dopaminergic neurons when those cells originate from the midbrain or ganglionic eminence, not from other brain regions. This indicates that a cell's ability to respond to Nurr1 is strictly limited by its early developmental location. The study confirms that Nurr1 can promote dopaminergic fate in embryonic stem cells but highlights regional restrictions in adult and cortical precursors.
- Nurr1 induces dopaminergic neurons only in midbrain and ganglionic eminence precursors.
- Cortical and spinal cord precursors do not respond to Nurr1-induced dopaminergic differentiation.
- Adult subventricular zone precursors also fail to convert to dopaminergic neurons via Nurr1.
- Nurr1's ability to drive dopaminergic fate is restricted by early regional specification.
- Embryonic stem cells remain responsive to Nurr1 for dopaminergic differentiation.
Cocaine modulates the expression of transcription factors related to the dopaminergic system in zebrafish.
Barreto-Valer K, López-Bellido R, Rodríguez RE
Cocaine exposure disrupts the normal development of dopaminergic neurons in zebrafish embryos by altering the expression and distribution of key transcription factors like Nurr1, Lmx1b, and Otp. These molecular changes lead to inconsistent levels of tyrosine hydroxylase, indicating that cocaine interferes with the genetic pathways required for building a healthy dopamine system.
- Cocaine alters gene expression in zebrafish embryos during critical developmental windows.
- Key dopaminergic transcription factors Nurr1, Lmx1b, and Otp show changed spatial distribution.
- Tyrosine hydroxylase levels fluctuate unpredictably after cocaine exposure.
- The study confirms these drugs disrupt early nervous system formation in a model organism.
Effects of early life permethrin exposure on spatial working memory and on monoamine levels in different brain areas of pre-senescent rats.
Nasuti C, Carloni M, Fedeli D, Gabbianelli R, Di Stefano A, Serafina CL, Silva I, Domingues V, Ciccocioppo R
Early-life exposure to the pesticide permethrin causes long-term cognitive deficits and dopamine depletion in rat brains. These findings suggest that environmental toxins may damage the neural circuits involved in working memory and motor control.
- Permethrin exposure during development reduces dopamine levels in the striatum of rats.
- Treated rats show specific impairments in spatial working memory tasks later in life.
- The study uses an animal model, not human participants or clinical data.
- No direct evidence links this pesticide effect to NR4A2-related syndromes.
Directed differentiation of human embryonic stem cell-line HUES9 to dopaminergic neurons in a serum-free defined culture niche.
Datta I, Ganapathy K, Tattikota SM, Bhonde R
Researchers develop a serum-free protocol to convert human embryonic stem cells into dopaminergic neurons with high purity. The method uses specific growth factors to guide cell differentiation, resulting in cells that express key dopaminergic markers like Nurr1 and tyrosine hydroxylase.
- The study uses human embryonic stem cells, not patient samples or clinical data.
- It establishes a laboratory protocol for generating dopaminergic neurons in vitro.
- Nurr1 (NR4A2) expression is confirmed as part of the differentiation process.
- No treatment or genetic intervention for NR4A2 syndrome is tested or proposed.