ErbB1-4-dependent EGF/neuregulin signals and their cross talk in the central nervous system: pathological implications in schizophrenia and Parkinson's disease

Iwakura, Yuriko; Nawa, Hiroyuki

doi:10.3389/fncel.2013.00004

Cited by 115 publications

(107 citation statements)

References 158 publications

(183 reference statements)

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“…It has been demonstrated in hematological diseases including myelodysplastic syndromes and leukemia [50, 51] and other neurological diseases [52]. PLCβ1 and phosphoinositide 3-kinase (PI3K) share the common substrate PIP2.…”

Section: Discussionmentioning

confidence: 99%

“…ERBB4 protein is a tyrosine-protein kinase and a member of the epidermal growth factor receptor subfamily, which contributes to glioma pathogenesis. At the protein level, typical ERBB4 signaling in the central nervous system involves downstream PLC and PI3K-AKT activation; cleaved intracellular fragment translocates into nucleus and regulates gene transcription [52]; cleaved ERBB4 protein also plays an important role in regulating the timing of astrogenesis in the developing brain [55]. It is worth to mention that ERBB4 expression is mainly restricted within neurons [56, 57] like PLCβ1 does among mature rodent brains, not commonly expressing a high level among astrocytes.…”

Section: Discussionmentioning

confidence: 99%

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Phospholipase C Beta 1: a Candidate Signature Gene for Proneural Subtype High-Grade Glioma

Chang

Liu

et al. 2015

Mol Neurobiol

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Phospholipase C beta 1 (PLCβ1) expresses in gliomas and cultured glial cells, but its expression is barely detectable in normal glial cells. We analyzed data from Gene Expression Omnibus (GEO-GDSxxx), The Cancer Genome Atlas (TCGA), and the Repository for Molecular Brain Neoplasia Data (REMBRANDT) to explore the potential role of PLCβ1 as a biomarker in high-grade glioma (HGG). PLCβ1 expression is significantly higher in grade III gliomas than that in grade IV gliomas from GDS1815 (n = 24 vs. 76), GDS1962 (n = 19 vs. 81), and GDS1975 (n = 26 vs. 59). In GDS1815, PLCβ1 expression correlates with several known proneural (PN) signature genes; its expression from PN subtype (n = 15) is significantly higher than that from mesenchymal (Mes) subtype (n = 33) HGG. In GDS1962, PLCβ1 expression is the highest in nontumor brain tissue (n = 23) and is significantly higher than its expression in grade II gliomas [astrocytomas (n = 7) and oligodendrogliomas (n = 37)]. A Kaplan-Meier survival curve from a REMBRANDT cohort demonstrates that glioma patients with intermediate PLCβ1 expression (n = 103) survived significantly longer than PLCβ1 downregulated (2X) groups (n = 226). From TCGA data, PLCβ1 RNA-Seq signal inversely correlates with the pathological grades, and PLCβ1 expression in PN (n = 8) is of significantly higher levels than that in Mes (n = 8) subtypes of glioblastoma. The top 50 % of PLCβ1 expression subgroup (n = 294) of gliomas (grades II to IV merged) survived significantly longer than the low 50 percentile of the PLCβ1 expression subgroup (n = 293). p values are less than 0.05 for all these analyses. We conclude that PLCβ1 is a candidate signature gene for PN subtype HGG, and its expression inversely correlates with glioma pathological grade and is a potential prognostic factor.Electronic supplementary materialThe online version of this article (doi:10.1007/s12035-015-9518-2) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Phospholipase C Beta 1: a Candidate Signature Gene for Proneural Subtype High-Grade Glioma

Chang

Liu

et al. 2015

Mol Neurobiol

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“…It is followed by a very timely review of current knowledge on the features of polysialic acid and their synthesizing enzymes (specially ST8SIA2), their functions in regulations of cell adhesion, ion channels, neurotrophins (such as BDNF) and catecholamine neurotransmitters (particularly dopamine), in light of several recent lines of evidence linking polysialic acid to schizophrenia (Sato and Kitajima, 2013). Iwakura and Nawa provide a very clear overview of the ErbB1-4 dependent EGF/neuregulin signals, their role in regulating the development and function of the central nervous system, and the contribution of deficits in ErbB signaling to schizophrenia and neurological disease (Iwakura and Nawa, 2013).Four articles discuss the animal model of schizophrenia, two of which address the Nrg1-cannabinoid interaction in a hypomorphic Nrg1 (Nrg1 HET) mouse model of schizophrenia. In an original study, Spencer et al investigated Nrg1-cannabinoid interaction in the hippocampus using proteomics, in which they identified alterations of some proteins involved in vesicular release of neurotransmitters, serotonergic neurotransmission, and growth factor release in response to Nrg1 hypomorphism and…”

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confidence: 99%

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confidence: 99%

Mapping the pathophysiology of schizophrenia: interactions between multiple cellular pathways

2014

Frontiers Research Topics

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Schizophrenia is a complex disorder involving dysregulation of multiple pathways in its pathophysiology with strong evidence to support roles for dopaminergic, glutamatergic, GABAergic, and cholinergic neurotransmitter systems and their interactions in the pathophysiology of the disorder (Benes, 2009;Karam et al., 2010;Gibbons et al., 2013). Additionally, evidence from genetic, post-mortem and animal studies over the past decade has identified a number of susceptibility factors for schizophrenia, including neuregulin 1 (Nrg1) and its receptor ErbB4, disrupted-in-schizophrenia-1 (DISK1), catechol-O-methyl transferase (COMT), BDNF, and Akt, along with their related pathways, that interact closely with dopaminergic, glutamatergic, and GABAergic neurotransmitter systems (Karam et al., 2010). Hence a key question is how these neurotransmitter systems and their interactions contribute to the pathophysiology of schizophrenia and whether interactive changes in these pathways occur in early brain development, based on the view of schizophrenia as a developmental disorder?This Frontier Research Topic has brought together leading experts in the field to address these questions from different angles in nine reviews, one theoretic article and two research articles. The first four articles focus on the roles and interactions of neurotransmitters in the pathophysiology of psychiatric disorders. Snyder and Gao (2013) provide an excellent review of NMDA receptor hypofunction hypothesis, suggesting NMDA receptor hypofunction as a convergence point for progression and symptoms of schizophrenia. They also discuss evidence on altered NMDA receptor subunits in schizophrenia and how these alterations interact with multiple schizophrenia susceptibility genes that lead to NMDA receptor dysfunction during development (Snyder and Gao, 2013). Scarr et al. (2013) present an in depth and very detailed coverage of cholinergic involvement in schizophrenia and how it interacts with other neurotransmitters including glutamate, dopamine, GABA and serotonin, as well as its links with the inflammatory/immune system. The review also provides a frame work for testable hypotheses of the potential outcomes of a dysregulated cholinergic system for research into the pathophysiologies of psychiatric disorders . Cognitive deficits are considered core symptoms of schizophrenia, while abnormalities in gamma oscillations have been identified in schizophrenia patients that are associated with deficits in attention, working memory, and other cognitive functions (Uhlhaas and Singer, 2010). Furth et al. (2013) reviewed the central role of dopamine D4 receptor in the generation of gamma frequency synchronization of neural networks and cognitive processes via their influence on parvalbumin-expressing GABAergic interneurons. They also examined their close synergistic relationship with neuregulin/ErbB4 signaling, in particular in the prefrontal cortex and hippocampus two major brain regions implicated in schizophrenia (Furth et al., 2013). Furthermore, there has been...

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“…The NRG1 and ERBB4 genes were identified as major susceptibility genes for schizophrenia by many association studies in several ethnic groups (Liu et al, 2005;Nicodemus et al, 2010;Stefanis et al, 2013;Stefansson et al, 2002). Furthermore, impaired NRG1-ErbB4 signalling is associated with cortical dysfunction, cognitive deficits and schizophrenia symptoms Iwakura and Nawa, 2013;Law et al, 2012;Mei and Xiong, 2008;Rico and Marin, 2011).…”

Section: Introductionmentioning

confidence: 99%

Differential effects of short- and long-term antipsychotic treatment on the expression of neuregulin-1 and ErbB4 receptors in the rat brain

Deng

Pan

et al. 2015

Psychiatry Research

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Neuregulin-1 (NRG1) and ErbB4 genes have been identified as candidate genes for schizophrenia. Postmortem studies indicated that NRG1-ErbB4 signalling is impaired in schizophrenia subjects. This study investigated whether short-or long-term antipsychotic treatment has different effects on the expression of NRG1 and ErbB4 receptors. Female Sprague-Dawley rats were treated orally with either aripiprazole (0.75 mg/kg), haloperidol (0.1 mg/kg), olanzapine (0.5 mg/kg), or vehicle, 3 times/day for 1 or 12 weeks. Western blotting was performed to examine the expression of NRG1 isoforms (135 kDa, 70 kDa and 40 kDa) and ErbB4 receptors. Both 1-week haloperidol and olanzapine treatment increased NRG1-70 kDa expression in the hippocampus; haloperidol also up-regulated ErbB4 levels in the prefrontal cortex (PFC). In the 12-week group, aripiprazole decreased the expression of all three NRG1 isoforms and ErbB4 receptors in the PFC, NRG1-70 kDa and -40 kDa in the cingulate cortex (Cg), and NRG1-135 kDa, -70 kDa and ErbB4 receptors in the hippocampus; haloperidol reduced NRG1-135 kDa in the PFC, NRG1-40 kDa in all three brain regions, and ErbB4 receptor levels in the PFC and hippocampus; NRG1-40 kDa in the PFC and Cg was also downregulated by olanzapine. These results suggest that the time-dependent and region-specific effects of antipsychotics on NRG1-ErbB4 signalling may contribute to the efficacy of antipsychotics to treat schizophrenia. AbstractNeuregulin-1 (NRG1) and ErbB4 genes have been identified as candidate genes for schizophrenia. Post-mortem studies indicated that NRG1-ErbB4 signalling is impaired in schizophrenia subjects. This study investigated whether short-or long-term antipsychotic treatment has different effects on the expression of NRG1 and ErbB4 receptors. Female Sprague-Dawley rats were treated orally with either aripiprazole (0.75mg/kg), haloperidol (0.1mg/kg), olanzapine (0.5mg/kg), or vehicle, 3 times/day for 1 or 12 weeks. Western blotting was performed to examine the expression of NRG1 isoforms (135kDa, 70kDa and 40kDa) and ErbB4 receptors. Both 1-week haloperidol and olanzapine treatment increased NRG1-70kDa expression in the hippocampus; haloperidol also up-regulated ErbB4 levels in the prefrontal cortex (PFC). In the 12-week group, aripiprazole decreased the expression of all three NRG1 isoforms and ErbB4 receptors in the PFC, NRG1-70kDa and -40kDa in the cingulate cortex (Cg), and NRG1-135kDa, -70kDa and ErbB4 receptors in the hippocampus; haloperidol reduced NRG1-135kDa in the PFC, NRG1-40kDa in all three brain regions, and ErbB4 receptor levels in the PFC and hippocampus; NRG1-40kDa in the PFC and Cg was also down-regulated by olanzapine. These results suggest that the time-dependent and regionspecific effects of antipsychotics on NRG1-ErbB4 signalling may contribute to the efficacy of antipsychotics to treat schizophrenia.

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ErbB1-4-dependent EGF/neuregulin signals and their cross talk in the central nervous system: pathological implications in schizophrenia and Parkinson's disease

Cited by 115 publications

References 158 publications

Phospholipase C Beta 1: a Candidate Signature Gene for Proneural Subtype High-Grade Glioma

Phospholipase C Beta 1: a Candidate Signature Gene for Proneural Subtype High-Grade Glioma

Mapping the pathophysiology of schizophrenia: interactions between multiple cellular pathways

Differential effects of short- and long-term antipsychotic treatment on the expression of neuregulin-1 and ErbB4 receptors in the rat brain

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