Neuregulin1-induced cell migration is impaired in schizophrenia: association with neuregulin1 and catechol-o-methyltransferase gene polymorphisms

Sei, Yoshitatsu; Ren-Patterson, Renee F.; Li, Z; Tunbridge, Elizabeth M.; Egan, Michael; Kolachana, Bhaskar; Weinberger, Daniel R.

doi:10.1038/sj.mp.4001994

Cited by 70 publications

(71 citation statements)

References 59 publications

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“…In schizophrenia, we propose that the increased expression of ErbB4 CYT-1 receptors and the increased fraction of CYT-1 to CYT-2 in the brain, combined with increased PIK3CD, create a molecular shift toward an attenuated NRG1-ErbB4-PI3K signaling system. This proposal is consistent with evidence showing impaired NRG1-mediated phosphorylation of AKT1 in patient-derived cells included in this study (53) and AKT1 dysfunction in schizophrenia (45,46). It is also noteworthy that reduced ErbB3 gene expression is observed in brain and LCLs of patients with schizophrenia (ref.…”

Section: Discussionsupporting

confidence: 76%

Neuregulin 1-ErbB4-PI3K signaling in schizophrenia and phosphoinositide 3-kinase-p110δ inhibition as a potential therapeutic strategy

Law

Wang

Sei

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

138

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Neuregulin 1 (NRG1) and ErbB4, critical neurodevelopmental genes, are implicated in schizophrenia, but the mediating mechanisms are unknown. Here we identify a genetically regulated, pharmacologically targetable, risk pathway associated with schizophrenia and with ErbB4 genetic variation involving increased expression of a PI3K-linked ErbB4 receptor (CYT-1) and the phosphoinositide 3-kinase subunit, p110δ (PIK3CD). In human lymphoblasts, 3,4,5 triphosphate [PI(3,4,5)P3] signaling is predicted by schizophrenia-associated ErbB4 genotype and PIK3CD levels and is impaired in patients with schizophrenia. In human brain, the same ErbB4 genotype again predicts increased PIK3CD expression. Pharmacological inhibition of p110δ using the small molecule inhibitor, IC87114, blocks the effects of amphetamine in a mouse pharmacological model of psychosis and reverses schizophrenia-related phenotypes in a rat neonatal ventral hippocampal lesion model. Consistent with these antipsychotic-like properties, IC87114 increases AKT phosphorylation in brains of treated mice, implicating a mechanism of action. Finally, in two family-based genetic studies, PIK3CD shows evidence of association with schizophrenia. Our data provide insight into a mechanism of ErbB4 association with schizophrenia; reveal a previously unidentified biological and disease link between NRG1-ErbB4, p110δ, and AKT; and suggest that p110δ is a previously undescribed therapeutic target for the treatment of psychiatric disorders.S chizophrenia is a severe neuropsychiatric disorder with a complex genetic etiology (1). Polymorphisms in the secreted growth factor neuregulin 1 (NRG1) have been associated with risk for schizophrenia (2-4) and recently, common genetic variation and structural microdeletions in ErbB4, a receptor tyrosine kinase for NRG1, have also been associated with the disorder (5-9). NRG1-ErbB4 signaling plays a critical role in neural development and synaptic plasticity (10-12) and NRG1 and ErbB4 mutant mice exhibit behavioral alterations (2, 12-14) consistent with other murine models of schizophrenia (15). Schizophrenia-associated genetic variation in these genes is implicated in human brain structure and function (6,16,17), but the biological mechanisms accounting for these diverse effects and how they translate into illness are unclear.Increased NRG1 and ErbB4 expression has been observed in schizophrenia postmortem brain tissue (5, 7, 18) and in neurons derived from induced pluripotent stem cells (IPSCs) of patients (19). Risk-associated polymorphisms in these genes affect expression of specific NRG1 and ErbB4 isoforms in human brain (7,18,20). In particular, risk polymorphisms in ErbB4 (rs7598440, rs839523, and rs707284) predict increased expression of the ErbB4 CYT-1 receptor (5, 7), one of two biologically occurring ErbB4 isoforms, the other being ErbB4 CYT-2 (21). Unlike ErbB4 CYT-2, ErbB4 CYT-1 includes a phosphoinositide 3-kinase (PI3K)-binding site and is capable of activating the PI3K pathway (21-24). Class IA PI3Ks are activated by recepto...

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Section: Discussionsupporting

confidence: 76%

Neuregulin 1-ErbB4-PI3K signaling in schizophrenia and phosphoinositide 3-kinase-p110δ inhibition as a potential therapeutic strategy

Law

Wang

Sei

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

138

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“…Consistent with basic models suggesting deficits in AKT phosphorylation and signaling underlying cognitive deficits (5, 7, 8), the A allele at rs1130233 associated with poorer cognitive func- tion and relative deficits in neuroimaging measures correspondingly evidenced reduced levels of AKT1 in the lymphoblasts of a subset of the same individuals (Figure 1). Thus, within the constraints of biological differences in the expression of physiological function between cell types, lymphoblasts potentially provide a useful model to test the functional status of genetic variation in the same living human subjects evaluated with neurocognitive tests and neuroimaging (65). This is exemplified here by genetically mediated differences in AKT1 protein abundance, assumed to reflect similar differences at the level of brain.…”

Section: Discussionmentioning

confidence: 95%

“…Epstein-Barr virus-transformed B lymphoblasts from a subgroup of 32 healthy controls (19 individuals with AKT1 SNP rs1130233 G/G and 13 individuals with A alleles) were prepared and AKT1 protein levels were analyzed by immunoblot (65). In brief, proteins extracted in buffer containing 250 mM Tris-HCl (pH 7.4), 100 mM NaCl, 1% Triton X-100, 0.1% SDS, 0.5% deoxycholic acid, 1 mM p-nitrophenylguanidinobenzoate, and protease inhibitor cocktails I and II (Sigma-Aldrich) were separated using SDS-PAGE on 4%-12% Tris-Glycine gel (Invitrogen).…”

Section: Methodsmentioning

confidence: 99%

Genetic variation in AKT1 is linked to dopamine-associated prefrontal cortical structure and function in humans

Tan¹,

Nicodemus²,

Chen³

et al. 2008

J. Clin. Invest.

131

191

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AKT1-dependent molecular pathways control diverse aspects of cellular development and adaptation, including interactions with neuronal dopaminergic signaling. If AKT1 has an impact on dopaminergic signaling, then genetic variation in AKT1 would be associated with brain phenotypes related to cortical dopaminergic function. Here, we provide evidence that a coding variation in AKT1 that affects protein expression in human B lymphoblasts influenced several brain measures related to dopaminergic function. Cognitive performance linked to frontostriatal circuitry, prefrontal physiology during executive function, and frontostriatal graymatter volume on MRI were altered in subjects with the AKT1 variation. Moreover, on neuroimaging measures with a main effect of the AKT1 genotype, there was significant epistasis with a functional polymorphism (Val158Met) in catechol-O-methyltransferase [COMT], a gene that indexes cortical synaptic dopamine. This genetic interaction was consistent with the putative role of AKT1 in dopaminergic signaling. Supportive of an earlier tentative association of AKT1 with schizophrenia, we also found that this AKT1 variant was associated with risk for schizophrenia. These data implicate AKT1 in modulating human prefrontal-striatal structure and function and suggest that the mechanism of this effect may be coupled to dopaminergic signaling and relevant to the expression of psychosis. IntroductionDopaminergic abnormalities have long served as a major framework for understanding the pathophysiology as well as pharmacology of psychosis, such as schizophrenia, and also associated cognitive deficits, particularly those affecting executive function and working memory. Classically, D1 receptors, implicated in the maintenance of relevant information during the working memory delay period (1), couple through Gα s protein to stimulate the production of cAMP and the activity of PKA (2). Conversely, D2 receptors, which in neural models play critical roles marking salience, prediction errors, and updating and manipulating new information (3), couple through Gα i/o protein to reduce cAMP production and PKA activity (2). Downstream from PKA, dopamine-(DA-) and cAMPregulated phosphoprotein of molecular weight 32 (DARPP-32) is a key signaling integrator that regulates an array of subsequent neurophysiological processes (2). Genetic variation in DARPP-32 has recently been found to have an impact on normal human variation in frontostriatal cognitive performance, neostriatal volume and physiologic activation, and functional connectivity between striatum and prefrontal cortex; DARPP-32 has also been implicated in risk for schizophrenia (4). The cAMP/PKA/DARPP-32 pathway, however, is not the only molecular network that transduces DA signals in dopaminoceptive neurons (2).

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“…In fact, it has been reported that NRG-1-induced cell migration resulting from ErbB-Akt signaling is impaired in immortalized lymphocyte from patients with schizophrenia. 32 Further studies are required to assess whether immortalized lymphocytes are a good tool to determine the effect of genetic risks on their gene expression and whether immortalized lymphocytes are an appropriate alternative to neuronal tissue. Dysbindin-1 and NRG-1 expression in lymphoblasts H Yamamori et al…”

Section: Discussionmentioning

confidence: 99%

Dysbindin-1 and NRG-1 gene expression in immortalized lymphocytes from patients with schizophrenia

et al. 2011

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The dysbindin-1 and neuregulin-1 (NRG-1) genes are related to schizophrenia. Expression studies in postmortem brains have revealed lower expression of dysbindin-1 and higher expression of NRG-1 in brain tissue from subjects with schizophrenia. In addition to the difficulty of sampling, the use of postmortem brain tissues is not ideal because these tissues are heterogeneous with respect to biochemical parameters, lifetime history of medications and physiological status at the time of death. In contrast, medication and environmental influences that could mask the genetic basis of differences in RNA expression are removed in immortalized lymphocytes by culturing. Only a few microarray analysis studies using immortalized lymphocytes in schizophrenia have been reported, and whether immortalized lymphocytes are an appropriate alternative to neuronal tissue remains controversial. In this study, we measured the mRNA expression levels of dysbindin-1, NRG-1 and two other genes (NPY1R and GNAO1) in immortalized lymphocytes from 45 patients with schizophrenia and 45 controls using real-time quantitative reverse transcriptase-PCR. No difference was observed between patients and controls with respect to the expression of dysbindin-1, NRG-1, NPY1R or GNAO1 gene. Our findings suggest that the gene expression profile of immortalized lymphocyte from schizophrenic patients is different from that in postmortem brain tissue at least with respect to the dysbindin-1 and NRG-1 genes. Journal of Human Genetics INTRODUCTIONSchizophrenia is a complex genetic disorder that is characterized by profound disturbances of cognition, emotion and social functioning. It affects B1% of the general population world wide. The dysbindin-1 and neuregulin-1 (NRG-1) genes are related to schizophrenia, 1 and the dysbindin-1 gene is also associated with cognitive functions. [2][3][4] Furthermore, the Sandy mouse, which expresses no dysbindin-1, has been reported to have behavioral abnormalities, cognitive deficits and a synaptic dysfunction that is related to the pathophysiology of schizophrenia. [5][6][7] Identified risk variants of NRG-1 are associated with the reduced white matter volume that is observed in schizophrenic brains. 8 The NRG-1 gene spans 1.2 Mb 9 and gives rise to many structurally and functionally distinct isoforms, through alternative promoter usage. These isoforms are divided into three classic groups: 10 type I (previously known as acetylcholine receptor inducing activity, heregulin or neu differentiation factor), type II (glia growth factor) and type III (cysteine-rich domain containing), which are based on distinct amino termini. Additional NRG-1 5¢ exons have

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Neuregulin1-induced cell migration is impaired in schizophrenia: association with neuregulin1 and catechol-o-methyltransferase gene polymorphisms

Cited by 70 publications

References 59 publications

Neuregulin 1-ErbB4-PI3K signaling in schizophrenia and phosphoinositide 3-kinase-p110δ inhibition as a potential therapeutic strategy

Neuregulin 1-ErbB4-PI3K signaling in schizophrenia and phosphoinositide 3-kinase-p110δ inhibition as a potential therapeutic strategy

Genetic variation in AKT1 is linked to dopamine-associated prefrontal cortical structure and function in humans

Dysbindin-1 and NRG-1 gene expression in immortalized lymphocytes from patients with schizophrenia

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