NURR1 Mutations in cases of schizophrenia and manic-depressive disorder

Buervenich, Silvia; Carmine, Andrea; Arvidsson, Mariette; Xiang, Fengqing; Zhang, Zhiping; Sydow, Olof; Jönsson, Erik G.; Sedvall, Göran; Leonard, Sherry; Ross, Randal G.; Freedman, Robert; Chowdari, Kodavali V.; Nimgaonkar, Vishwajit L.; Perlmann, Thomas; Anvret, Maria; Olson, Lar̀s

doi:10.1002/1096-8628(20001204)96:6<808::aid-ajmg23>3.0.co;2-e

Cited by 137 publications

(96 citation statements)

References 28 publications

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“…16,19,20 In addition, a Nurr1 mutation has been demonstrated in a few schizophrenic patients. 22 Recently, a reduction of Nurr1 expression in the pFCx was found both in schizophrenia and bipolar disorder. 23 The spontaneous locomotor activity was significantly higher in Nurr1 heterozygous ( þ /À) male and female mice (Figures 1 and 2) compared to the control wild-type mice.…”

Section: Discussionmentioning

confidence: 99%

“…Given the role of Nurr1 in shaping the DA phenotype, it is conceivable that Nurr1 mutations could play a role in a chronic disorder such as schizophrenia and/or bipolar disorders. 22,23 Nurr1 ( þ /À) mice that survive until adulthood are fertile and display no apparent physical defects. Nurr1 ( þ /À) mice have decreased DA levels at 2 months after birth but at 5 months striatal DA is normalized.…”

Section: Introductionmentioning

confidence: 99%

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Adult mice with reduced Nurr1 expression: an animal model for schizophrenia

et al. 2007

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The transcription factor Nurr1 (NR4A2) has been found to play a critical role in the development of midbrain dopaminergic neurons. Nurr1 heterozygous ( þ /À) male and female mice expressing 35-40% of normal levels of Nurr1 were generated and examined in animal models related to symptoms of schizophrenia. The Nurr1 ( þ /À) mice displayed hyperactivity in a novel environment, which persisted after administration of the dopamine-mimetic amphetamine and the N-methyl-D-aspartate receptor antagonist phencyclidine. The Nurr1 ( þ /À) mice were deficient in the retention of emotional memory and showed an enhanced response to swim stress. In addition, Nurr1 ( þ /À) male mice displayed a reduced dopamine turnover in the striatum and an enhanced dopamine turnover in the prefrontal cortex, while female mice showed an opposite pattern. These results show that Nurr1 ( þ /À) mice display a pattern of behaviors indicative of potential relevance for symptoms of schizophrenia combined with a gender-specific abnormal dopamine transmission in the striatum and prefrontal cortex, respectively. This suggests that the Nurr1 mutant mouse may be a potential animal model for studies on some of the behavioral and molecular mechanisms underlying schizophrenia.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Adult mice with reduced Nurr1 expression: an animal model for schizophrenia

et al. 2007

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“…In the proposed transcriptional circuit INFS co‐ordinates incoming developmental signals (St) through the Feed‐Forward (FF) module and reinforces or turns off those input signals via a feedback (FB) module (Lee et al, 2012). *marks signaling pathways in which schizophrenia‐linked genes a have been found, including cAMP, G‐protein signaling, PKC, MAPK, NfkB, CREB, RXR, and Nurr1 (Buervenich et al, 2000; Sun et al, 2010; Jablensky et al, 2011). In schizophrenia and other neurodevelopmental diseases, mutations of these individual genes, including “weak” copy variations could deregulate this auto‐regulated genomic circuit (red lines) and thus lead to broad molecular and developmental dysfunctions (Figure is based on information in (Stachowiak et al, 2013) and in (Terranova et al, 2015) and linked database).…”

Section: Role Of Nfgfr1 In Diseasementioning

confidence: 99%

Evidence‐Based Theory for Integrated Genome Regulation of Ontogeny—An Unprecedented Role of Nuclear FGFR1 Signaling

Stachowiak

2016

Journal Cellular Physiology

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Genetic experiments have positioned the fgfr1 gene at the top of the gene hierarchy that governs gastrulation, as well as the subsequent development of the major body axes, nervous system, muscles, and bones, by affecting downstream genes that control the cell cycle, pluripotency, and differentiation, as well as microRNAs. Studies show that this regulation is executed by a single protein, the nuclear isoform of FGFR1 (nFGFR1), which integrates signals from development‐initiating factors, such as retinoic acid (RA), and operates at the interface of genomic and epigenomic information. nFGFR1 cooperates with a multitude of transcriptional factors (TFs), and targets thousands of genes encoding for mRNAs, as well as miRNAs in top ontogenic networks. nFGFR1 binds to the promoters of ancient proto‐oncogenes and tumor suppressor genes, in addition to binding to metazoan morphogens that delineate body axes, and construct the nervous system, as well as mesodermal and endodermal tissues. The discovery of pan‐ontogenic gene programming by integrative nuclear FGFR1 signaling (INFS) impacts our understanding of ontogeny, as well as developmental pathologies, and holds new promise for reconstructive medicine, and cancer therapy. J. Cell. Physiol. 231: 1199–1218, 2016. © 2016 The Authors. Journal of Cellular Physiology published by Wiley Periodicals, Inc.

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“…Together with other seminal transcription factors such as Pitx3 and Lmx1b, Nurr1 also exerts a number of functions in postmitotic and mature mesencephalic dopamine neurons, including regulation of tyrosine hydroxylase (TH) and dopamine transporter (DAT) (Saucedo-Cardenas et al, 1998;Kadkhodaei et al, 2009). Nurr1 has also immunomodulatory roles by functioning as transcriptional repressor of proinflammatory genes (Saijo et al, 2009), and altered Nurr1 expression has been implicated in dopamine-associated brain disorders, including Parkinson's disease , attention deficit/hyperactivity disorder (ADHD) (Smith et al, 2005), and schizophrenia (Buervenich et al, 2000;Xing et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Prenatal Immune Activation Interacts with GeneticNurr1Deficiency in the Development of Attentional Impairments

Vuillermot

Joodmardi²,

Perlmann³

et al. 2012

J. Neurosci.

117

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Prenatal exposure to infection has been linked to increased risk of neurodevelopmental brain disorders, and recent evidence implicates altered dopaminergic development in this association. However, since the relative risk size of prenatal infection appears relatively small with respect to long-term neuropsychiatric outcomes, it is likely that this prenatal insult interacts with other factors in shaping the risk of postnatal brain dysfunctions. In the present study, we show that the neuropathological consequences of prenatal viral-like immune activation are exacerbated in offspring with genetic predisposition to dopaminergic abnormalities induced by mutations in Nurr1, a transcription factor highly essential for normal dopaminergic development. We combined a mouse model of heterozygous genetic deletion of Nurr1 with a model of prenatal immune challenge by the viral mimetic poly(I:C) (polyriboinosinic polyribocytidilic acid). In our gene-environment interaction model, we demonstrate that the combination of the genetic and environmental factors not only exerts additive effects on locomotor hyperactivity and sensorimotor gating deficits, but further produces synergistic effects in the development of impaired attentional shifting and sustained attention. We further demonstrate that the combination of the two factors is necessary to trigger maldevelopment of prefrontal cortical and ventral striatal dopamine systems. Our findings provide evidence for specific geneenvironment interactions in the emergence of enduring attentional impairments and neuronal abnormalities pertinent to dopamineassociated brain disorders such as schizophrenia and attention deficit/hyperactivity disorder, and further emphasize a critical role of abnormal dopaminergic development in these etiopathological processes.

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NURR1 Mutations in cases of schizophrenia and manic-depressive disorder

Cited by 137 publications

References 28 publications

Adult mice with reduced Nurr1 expression: an animal model for schizophrenia

Adult mice with reduced Nurr1 expression: an animal model for schizophrenia

Evidence‐Based Theory for Integrated Genome Regulation of Ontogeny—An Unprecedented Role of Nuclear FGFR1 Signaling

Prenatal Immune Activation Interacts with GeneticNurr1Deficiency in the Development of Attentional Impairments

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