Parathyroid hormone activates the orphan nuclear receptor Nurr1 to induce FGF23 transcription.
Meir T, Durlacher K, Pan Z, Amir G, Richards WG, Silver J, Naveh-Many T
Parathyroid hormone increases FGF23, a key hormone in bone and kidney health, by activating the Nurr1 protein in bone cells. In kidney disease, high PTH leads to more Nurr1, which drives excess FGF23; drugs that lower PTH also reduce Nurr1 and FGF23 levels.
- PTH boosts FGF23 by turning on Nurr1 in bone cells
- Nurr1 binds directly to the FGF23 gene to increase its activity
- In kidney disease, high PTH raises Nurr1 and FGF23
- Drugs that lower PTH also reduce Nurr1 and FGF23
- Targeting Nurr1 could help control FGF23 in disease
Effect of 17β-estradiol on striatal dopaminergic transmission induced by permethrin in early childhood rats.
Nasuti C, Carloni M, Fedeli D, Di Stefano A, Marinelli L, Cerasa LS, Meda C, Maggi A, Gabbianelli R
In male rats, giving 17β-estradiol worsened the damage to dopamine systems caused by early-life exposure to the pesticide permethrin, suggesting estrogen may not be protective in this context and could even make neurodevelopmental harm worse.
- Estrogen made pesticide-induced dopamine damage worse in young rats
- Permethrin may block estrogen's protective effects by targeting ERα and ERβ
- NR4A2 (Nurr1) gene expression dropped after pesticide exposure
- Estrogen treatment did not help and may have increased harm
- Findings suggest caution with estrogen use in early-life neurotoxicity
Efficient reprogramming of mouse fibroblasts to neuronal cells including dopaminergic neurons.
Oh SI, Park HS, Hwang I, Park HK, Choi KA, Jeong H, Kim SW, Hong S
Scientists turned mouse skin cells directly into functional neurons, including dopamine-producing neurons, using a combination of specific genes and growth factors. This approach could lead to new cell-based treatments for brain and spinal cord disorders like Parkinson's disease.
- Mouse skin cells were turned into neurons using key genes and growth factors
- The process produced dopamine-making neurons, relevant to Parkinson's
- Reprogrammed cells showed proper neuron shape and markers
- This method may help develop cell therapies for brain injuries and diseases
Characterization of claustral neurons by comparative gene expression profiling and dye-injection analyses.
Watakabe A, Ohsawa S, Ichinohe N, Rockland KS, Yamamori T
The claustrum shares key gene expression patterns with the neocortex, especially in primates, suggesting it may be a specialized part of the cortical system. Neurons in the claustrum express NURR1 and other cortical markers, and project to the cortex, indicating functional similarities to cortical neurons.
- Claustrum neurons share gene patterns with cortical neurons in primates
- NURR1 is highly expressed in claustrum and marks glutamatergic neurons
- Claustral neurons send projections to the cortex, like cortical neurons
- Migratory NURR1+ cells were seen in embryonic white matter
- Dendrites do not cross between claustrum and insular cortex
Monocytes and CD4+ T cells contribution to the under-expression of NR4A2 and TNFAIP3 genes in patients with multiple sclerosis.
Navone ND, Perga S, Martire S, Berchialla P, Malucchi S, Bertolotto A
In people with multiple sclerosis, monocytes show reduced levels of NR4A2 and TNFAIP3, two genes important for calming inflammation, which may contribute to disease activity. CD4+ T cells have a smaller role, with only a slight drop in NR4A2.
- Monocytes have low NR4A2 and TNFAIP3 in MS
- These genes help control inflammation
- Low levels may worsen MS symptoms
- CD4+ T cells play a minor role
- Findings may guide anti-inflammatory treatments
Impact of circadian nuclear receptor REV-ERBα on midbrain dopamine production and mood regulation.
Chung S, Lee EJ, Yun S, Choe HK, Park SB, Son HJ, Kim KS, Dluzen DE, Lee I, Hwang O, Son GH, Kim K
REV-ERBα regulates dopamine production in the brain's midbrain region and influences mood-related behaviors in mice by controlling the activity of the TH gene, which is also regulated by NURR1, the protein affected in NR4A2-related syndrome. This suggests that targeting REV-ERBα could help treat mood disorders linked to circadian rhythm disruptions.
- REV-ERBα controls dopamine production in the midbrain
- It suppresses TH gene activity by competing with NURR1
- Disrupting REV-ERBα causes mania-like behavior in mice
- This links circadian rhythms to mood regulation
- Potential new target for treating mood disorders
Dysregulation of dopaminergic regulatory mechanisms in the mesolimbic pathway induced by morphine and morphine withdrawal.
García-Pérez D, López-Bellido R, Rodríguez RE, Laorden ML, Núñez C, Milanés MV
Morphine use and withdrawal alter the activity of key brain genes (Nurr1 and Pitx3) that control dopamine production in the reward pathway, which may contribute to addiction-related changes in brain function. These changes happen without altering the number of dopamine neurons, suggesting the brain's wiring adapts through gene activity shifts.
- Morphine affects Nurr1 and Pitx3 genes in dopamine neurons
- These genes regulate dopamine production in the reward pathway
- Changes occur during addiction and withdrawal, not in neuron numbers
- Nurr1 and Pitx3 move into neuron nuclei during drug exposure
- This may drive long-term brain changes linked to addiction
Engineering of midbrain organoids containing long-lived dopaminergic neurons.
Tieng V, Stoppini L, Villy S, Fathi M, Dubois-Dauphin M, Krause KH
This study created 3D brain tissues from stem cells that contain long-lasting dopamine-producing neurons similar to those lost in Parkinson's disease. The method produces these neurons quickly and in high numbers, with features matching human midbrain neurons, including key proteins like NURR1. These tissues can be used to test drugs and study brain diseases.
- Creates midbrain-like dopamine neurons in 3 weeks
- Neurons express NURR1 and other key midbrain markers
- Tissues are electrically active and mature
- Can be used for drug testing and disease research
- Optimal results with specific timing and inhibitors
The lifelong maintenance of mesencephalic dopaminergic neurons by Nurr1 and engrailed.
Alavian KN, Jeddi S, Naghipour SI, Nabili P, Licznerski P, Tierney TS
Nurr1 and engrailed are critical transcription factors that maintain the health and function of dopamine-producing brain cells throughout life, and their failure is linked to Parkinson's disease. These proteins help these neurons survive, work properly, and resist degeneration.
- Nurr1 and engrailed keep brain dopamine cells alive and functioning
- They are essential for neuron survival and protection from degeneration
- Loss of these factors contributes to Parkinson's disease pathology
- These proteins help neurons maintain their identity and function
Inhibition of Methicillin-resistant Staphylococcus aureus-induced cytokines mRNA production in human bone marrow derived mesenchymal stem cells by 1,25-dihydroxyvitamin D3.
Maiti A, Jiranek WA
Vitamin D3 reduces inflammation in human bone stem cells infected with MRSA by blocking a key inflammatory pathway and restoring protective gene silencing marks. This suggests vitamin D3 may help protect bone health during MRSA infections.
- Vitamin D3 blocks harmful inflammation in bone stem cells
- It stops the activation of NF-κB, a major inflammation trigger
- Vitamin D3 restores histone marks that silence inflammatory genes
- NR4A2 is upregulated during MRSA infection and reduced by vitamin D3
- This effect may help preserve bone-forming cell function
Orchestrated increase of dopamine and PARK mRNAs but not miR-133b in dopamine neurons in Parkinson's disease.
Schlaudraff F, Gründemann J, Fauler M, Dragicevic E, Hardy J, Liss B
In Parkinson's disease, dopamine neurons show increased levels of mRNAs linked to dopamine production and cellular cleanup systems, likely as a response to toxic alpha-synuclein buildup, but the microRNA miR-133b, previously tied to PD, remains unchanged in these neurons.
- Dopamine neurons in PD increase protective mRNAs
- Alpha-synuclein buildup triggers compensatory responses
- miR-133b levels are unchanged in PD neurons
- Findings suggest cellular resilience mechanisms
- No evidence of miR-133b dysregulation in human PD
Isolation of human induced pluripotent stem cell-derived dopaminergic progenitors by cell sorting for successful transplantation.
Doi D, Samata B, Katsukawa M, Kikuchi T, Morizane A, Ono Y, Sekiguchi K, Nakagawa M, Parmar M, Takahashi J
This study developed a method to isolate pure human stem cell-derived dopamine-producing cells using a specific marker, CORIN, which leads to safe and effective transplantation in animal models of Parkinson's disease. The best results came from cells in a stage that also expressed NURR1, a gene linked to NR4A2-related syndrome, suggesting potential relevance for future therapies.
- CORIN marker isolates pure dopamine progenitor cells
- Cells with NURR1 expression showed best survival and function
- Transplanted cells improved motor symptoms without tumors
- Method is scalable and safe for potential clinical use
- Findings may inform therapies for NR4A2/NURR1-related conditions
Regulation of NR4A by nutritional status, gender, postnatal development and hormonal deficiency.
Pérez-Sieira S, López M, Nogueiras R, Tovar S
NR4A genes, including NURR1 (NR4A2), are regulated by fasting, sex hormones, and development in fat tissue, which plays a key role in energy and glucose control. These findings suggest NR4A2 activity may be influenced by diet and hormonal changes, potentially affecting metabolic health in children with NR4A2-related syndrome.
- NR4A genes are turned up during fasting, even without leptin
- Male and female hormones affect NR4A levels differently
- NR4A2 activity in fat tissue impacts energy and glucose balance
- Changes in NR4A expression may affect metabolic health in NR4A2 syndrome
- Fasting and development strongly influence NR4A gene activity
Retraction for Kitagawa et al., 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 SI, Kato S, Freedman LP
This paper investigates how Nurr1, a protein encoded by the NR4A2 gene, interacts with the Wnt signaling pathway to regulate gene expression. The findings reveal a molecular mechanism that could influence brain development and function, potentially relevant to NR4A2-related disorders.
- Nurr1 interacts with Wnt signaling to control gene activity
- This interaction may affect brain development and function
- The mechanism could explain some features of NR4A2-related syndromes
Induction of neurotrophic and differentiation factors in neural stem cells by valproic acid.
Almutawaa W, Kang NH, Pan Y, Niles LP
Valproic acid increases the production of key neurotrophic factors and genes involved in dopamine neuron development in neural stem cells, likely through epigenetic changes. This suggests a potential mechanism for its neuroprotective and developmental effects.
- Valproic acid boosts CDNF and GDNF, important for neuron survival
- It increases Nurr1, a gene critical for dopamine neuron formation
- Effects are linked to histone hyperacetylation, an epigenetic change
- Results come from neural stem cells, not human patients
- May support neurodevelopmental benefits seen in some patients
Stress and glucocorticoid regulation of NR4A genes in mice.
Helbling JC, Minni AM, Pallet V, Moisan MP
NR4A2 (Nurr1) and related genes are rapidly activated in stress-response brain regions and adrenal glands in mice, and their activity is regulated by glucocorticoids, suggesting a key role in how the body responds to stress. This regulation may influence long-term stress adaptation and could inform treatments for disorders involving stress dysregulation.
- NR4A2 is strongly activated in adrenal glands and pituitary during stress
- Glucocorticoids control NR4A2 activity in stress-response areas
- NR4A2 activation is weak in higher brain regions like hippocampus and cortex
- NR4A2 regulation is disrupted in low-glucocorticoid models
- This pathway may affect stress-related neurological conditions
Exposure to atrazine during gestation and lactation periods: toxicity effects on dopaminergic neurons in offspring by downregulation of Nurr1 and VMAT2.
Sun Y, Li YS, Yang JW, Yu J, Wu YP, Li BX
Exposure to the pesticide atrazine during pregnancy and breastfeeding reduces dopamine levels and damages dopamine-producing neurons in rat offspring by lowering Nurr1 and VMAT2, two proteins critical for dopamine function and protection.
- Atrazine exposure harms offspring's dopamine neurons
- Nurr1 and VMAT2 levels drop after exposure
- Dopamine levels decrease in the brain
- Effects persist into adulthood
- Nurr1 is key to protecting dopamine neurons
Induction of dopaminergic neurons from human Wharton's jelly mesenchymal stem cell by forskolin.
Paldino E, Cenciarelli C, Giampaolo A, Milazzo L, Pescatori M, Hassan HJ, Casalbore P
Forskolin can turn human umbilical cord stem cells into dopamine-producing brain cells, which may offer a potential therapy for neurological conditions involving dopamine loss.
- Forskolin converts umbilical cord stem cells into dopamine neurons
- Key dopamine genes and proteins (Nurr1, TH) increase after treatment
- Cells release brain-protective factors linked to neuron survival
- This approach could help treat dopamine-related brain disorders
Nur77 suppresses pulmonary artery smooth muscle cell proliferation through inhibition of the STAT3/Pim-1/NFAT pathway.
Liu Y, Zhang J, Yi B, Chen M, Qi J, Yin Y, Lu X, Jasmin JF, Sun J
Nur77, a member of the NR4A family, acts as a brake on the abnormal growth of lung artery cells by blocking a key signaling pathway involved in pulmonary hypertension. This suggests that boosting Nur77 activity could be a potential treatment strategy for pulmonary arterial hypertension.
- Nur77 reduces lung artery cell overgrowth
- It blocks the STAT3/Pim-1/NFAT signaling pathway
- Nur77 levels rise in response to PAH triggers
- Activating Nur77 may treat pulmonary hypertension
- This pathway is a potential drug target
Foxa2 acts as a co-activator potentiating expression of the Nurr1-induced DA phenotype via epigenetic regulation.
Yi SH, He XB, Rhee YH, Park CH, Takizawa T, Nakashima K, Lee SH
Foxa2 helps Nurr1 turn on dopamine-producing genes in brain cells by preventing a repressor complex from shutting them down, leading to more open chromatin and stronger gene expression. This interaction is essential for developing dopamine neurons, which could inform therapies for Parkinson's and related disorders.
- Foxa2 boosts Nurr1's ability to activate dopamine genes
- Foxa2 blocks a repressor complex that silences dopamine genes
- Increased histone acetylation opens chromatin for gene expression
- This partnership is critical for dopamine neuron development
- Findings may guide cell therapies for Parkinson's disease
Angiotensin II receptor blockers differentially affect CYP11B2 expression in human adrenal H295R cells.
Matsuda K, Uruno A, Kogure N, Sugawara K, Shimada H, Nezu M, Saito-Ito T, Iki Y, Kudo M, Shimizu K, Sato I, Yoshikawa T, Satoh F, Ito R, Yokoyama A, Rainey WE, Saito-Hakoda A, Ito S, Sugawara A
Telmisartan, a type of blood pressure medication, increases aldosterone production in human adrenal cells by activating a gene called CYP11B2 through a pathway involving the NURR1 protein, independent of its usual blood pressure mechanism. This effect is linked to calcium signaling and may explain why some patients on telmisartan have higher aldosterone levels.
- Telmisartan boosts aldosterone-making gene activity
- Effect happens via NURR1, not through standard blood pressure receptors
- Calcium signaling is key to this process
- Other ARBs like olmesartan don’t have this effect
- May explain unexpected hormone changes in some patients
Functional roles of Nurr1, Pitx3, and Lmx1a in neurogenesis and phenotype specification of dopamine neurons during in vitro differentiation of embryonic stem cells.
Hong S, Chung S, Leung K, Hwang I, Moon J, Kim KS
Nurr1, Pitx3, and Lmx1a are key genes that guide the development of dopamine neurons, with each playing unique and overlapping roles: Nurr1 controls dopamine production, Pitx3 drives neuron formation, and Lmx1a supports both processes. These genes work together to shape dopamine neurons during early brain development.
- Nurr1 turns on dopamine-making genes
- Pitx3 helps make neurons, not just dopamine cells
- Lmx1a supports both neuron and dopamine development
- Each gene has distinct roles in building dopamine neurons
- These genes interact to shape brain cell identity
Nur transcription factors in stress and addiction.
Campos-Melo D, Galleguillos D, Sánchez N, Gysling K, Andrés ME
Nur transcription factors, including Nurr1 (NR4A2), play a key role in how the brain responds to stress and addiction by altering gene expression in reward and stress circuits. These factors are rapidly activated by stress and drugs, and their long-term changes may contribute to lasting brain dysfunction seen in chronic stress and addiction.
- Nurr1 (NR4A2) is activated by stress and addictive drugs
- It helps reprogram brain circuits involved in reward and stress
- Long-term changes in Nurr1 may drive lasting brain dysfunction
- Nurr1 is a key player in addiction and stress-related disorders
Twenty-Four Genes are Upregulated in Patients with Hypospadias.
Karabulut R, Turkyilmaz Z, Sonmez K, Kumas G, Ergun S, Ergun M, Basaklar A
This study found 24 genes, including NR4A2, that are overactive in penile tissue from boys with hypospadias, suggesting these genes may play a role in the condition's development. The findings highlight potential biological pathways involved in penile formation and could guide future research into causes and treatments.
- 24 genes are overactive in hypospadias penile tissue
- NR4A2 is among the upregulated genes
- These genes may disrupt normal penile development
- Findings could help identify disease causes and targets
- Further studies needed in larger patient groups
Nurr1 expression is regulated by voltage-dependent calcium channels and calcineurin in cultured hippocampal neurons.
Tokuoka H, Hatanaka T, Metzger D, Ichinose H
Neural activity boosts Nurr1 levels in brain cells through voltage-dependent calcium channels and the calcineurin pathway, suggesting a direct link between brain cell activity and Nurr1 regulation.
- Nurr1 increases when brain cells are more active
- Calcium entry through voltage-dependent channels triggers Nurr1 rise
- The enzyme calcineurin, not CaMK, is essential for this process
- This mechanism is specific to individual brain cells
- Activity-dependent Nurr1 control may influence brain development and function
The NR4A2 nuclear receptor is recruited to novel nuclear foci in response to UV irradiation and participates in nucleotide excision repair.
Jagirdar K, Yin K, Harrison M, Lim W, Muscat GE, Sturm RA, Smith AG
NR4A2 helps repair DNA damage caused by UV light by moving to sites of damage and working with other repair proteins. This process depends on specific parts of the NR4A2 protein and proper chromatin access, and boosting NR4A2 levels improves DNA repair.
- NR4A2 moves to DNA damage sites after UV exposure
- It works with key DNA repair proteins to fix UV damage
- Proper protein structure and chromatin access are needed for this repair role
- More NR4A2 leads to faster removal of DNA damage
- This suggests NR4A2 is a direct player in DNA repair
A melanocyte lineage program confers resistance to MAP kinase pathway inhibition.
Johannessen CM, Johnson LA, Piccioni F, Townes A, Frederick DT, Donahue MK, Narayan R, Flaherty KT, Wargo JA, Root DE, Garraway LA
This study found that melanoma cells can become resistant to BRAF and MEK inhibitors by activating a melanocyte-specific gene program involving NR4A2 and other transcription factors, which helps the cancer cells survive treatment. Blocking both the MAPK pathway and chromatin regulators can overcome this resistance.
- NR4A2 is part of a melanocyte program that causes drug resistance
- Activating cAMP and CREB pathways helps melanoma resist treatment
- Combining MAPK and histone-deacetylase inhibitors may overcome resistance
- Resistance is linked to melanocyte lineage genes, not just BRAF mutations
Cxcl12/Cxcr4 signaling controls the migration and process orientation of A9-A10 dopaminergic neurons.
Yang S, Edman LC, Sánchez-Alcañiz JA, Fritz N, Bonilla S, Hecht J, Uhlén P, Pleasure SJ, Villaescusa JC, Marín O, Arenas E
CXCL12/CXCR4 signaling guides the movement and proper wiring of dopamine-producing brain cells (A9-A10 neurons) during early development. This pathway helps these neurons migrate to their correct positions and extend their processes in the right direction.
- CXCL12 from brain coverings guides dopamine neuron migration
- CXCR4 on dopamine neurons responds to this signal
- Blocking CXCR4 traps neurons in the wrong brain layer
- Proper neuron positioning depends on this signaling system
- Disruption leads to miswired dopamine circuits
NURR1 in Parkinson disease--from pathogenesis to therapeutic potential.
Decressac M, Volakakis N, Björklund A, Perlmann T
NURR1 is a key protein that helps maintain the health and identity of dopamine-producing brain cells, and its dysfunction is linked to Parkinson's disease. Reduced NURR1 activity may contribute to early symptoms of Parkinson's before neurons die, making it a promising target for new treatments.
- NURR1 maintains dopamine neuron health
- NURR1 is reduced in Parkinson's-affected neurons
- NURR1 loss may cause early Parkinson's symptoms
- Boosting NURR1 could be a new treatment strategy
Low dose bexarotene treatment rescues dopamine neurons and restores behavioral function in models of Parkinson's disease.
McFarland K, Spalding TA, Hubbard D, Ma JN, Olsson R, Burstein ES
Low doses of the drug bexarotene protect dopamine neurons and improve movement in rat models of Parkinson's disease by activating Nurr1, a protein linked to dopamine neuron health. This suggests bexarotene could be a safe and effective treatment for Parkinson's in humans, with fewer side effects than high-dose cancer use.
- Bexarotene activates Nurr1, supporting dopamine neuron survival
- Low doses reverse brain and behavior damage in Parkinson's rats
- Side effects are much milder than in cancer treatment doses
- Human doses may be effective and well-tolerated
- Offers a potential therapy for Parkinson's disease
Detailed expression analysis of regulatory genes in the early developing human neural tube.
Marklund U, Alekseenko Z, Andersson E, Falci S, Westgren M, Perlmann T, Graham A, Sundström E, Ericson J
NR4A2 (Nurr1) is not a unique marker for dopamine neurons in humans, as it is also active in other midbrain neurons and stem cell cultures, suggesting its role may be broader than previously thought. This challenges assumptions about its specificity and could impact how we model or treat NR4A2-related disorders.
- NR4A2 is not exclusive to dopamine neurons in humans
- NR4A2 is active in other midbrain neuron types
- Human ventral spinal cord motor neurons come from two distinct progenitor types
- Human neural development has unique features not seen in mice or chickens
- These findings may affect stem cell models and therapies
NR4A nuclear receptors in immunity and atherosclerosis.
Hamers AA, Hanna RN, Nowyhed H, Hedrick CC, de Vries CJ
NR4A nuclear receptors, including Nurr1, play key roles in regulating immune responses and reducing atherosclerosis in mice, suggesting potential therapeutic targets for chronic inflammatory conditions.
- NR4A receptors regulate immune cell development and function
- Nurr1 reduces atherosclerosis in mouse models
- NR4A activity may influence chronic inflammation
- These receptors could be targets for treating inflammatory diseases
Constraining the Pluripotent Fate of Human Embryonic Stem Cells for Tissue Engineering and Cell Therapy - The Turning Point of Cell-Based Regenerative Medicine.
Parsons XH
This study shows that human embryonic stem cells can be efficiently turned into pure, high-quality neurons or heart muscle cells using simple chemicals like retinoic acid and nicotinamide. These cells are ideal for treating brain and heart damage because they are stable, safe, and can regenerate tissue. The method could accelerate the development of stem cell therapies for neurological and heart diseases.
- Retinoic acid turns stem cells into neurons via Nurr-1 activation
- Nicotinamide directs stem cells to become beating heart cells
- High purity and efficiency in generating therapy-ready cells
- Method enables large-scale production of clinical-grade cells
- Potential to treat brain and heart damage with regenerative therapies
Lmx1a encodes a rostral set of mesodiencephalic dopaminergic neurons marked by the Wnt/B-catenin signaling activator R-spondin 2.
Hoekstra EJ, von Oerthel L, van der Heide LP, Kouwenhoven WM, Veenvliet JV, Wever I, Jin YR, Yoon JK, van der Linden AJ, Holstege FC, Groot Koerkamp MJ, Smidt MP
Lmx1a controls a specific group of dopamine-producing brain cells in the front and side regions of the midbrain, and it does so by turning on a gene called Rspo2 that boosts a key signaling pathway needed for neuron development. Without Lmx1a, this pathway fails, leading to missing or defective dopamine neurons, similar to what happens in NR4A2-related disorders.
- Lmx1a regulates a key dopamine neuron group in the midbrain
- Lmx1a activates Rspo2, which boosts Wnt signaling
- Loss of Lmx1a disrupts dopamine neuron development
- Rspo2 loss mimics Lmx1a deficiency
- This pathway may be relevant to NR4A2-related syndromes