1Med. Hypotheses 2004 -1 62: 542-5
TitleIntrathecal therapy with trastuzumab may be beneficial in cases of refractory schizophrenia.
AbstractRefractory schizophrenia has limited therapeutic options. schizophrenia can be considered to be a disease of abnormal synaptic plasticity. Neuregulin is a member of the epithelial growth factor family, which induces growth and differentiation of epithelial, glial and muscle cells in culture. Neuregulin has been documented to be important in synaptic plasticity. The important role of neuregulin in synaptic plasticity as well as its developmental role have increasingly been documented recently. The actions of neuregulin are mediated through ERB receptors. Neuregulin can bind directly to ERBB3 and erbB4 receptors and receptor heterodimerization allows neuregulin dependent activation of erbB2. The role of Erb 2 could make it possible to use the monoclonal antibody against it for improving the synaptic plasticity through the action on neuregulin. The use of trastuzumab (Her2 antibody) as targeted therapy is well documented in metastatic carcinoma of breast. Also intra-thecal administration of trastuzumab has been reported to be safe in carcinomatous meningitis. Here it is being hypothesized that intra-thecal administration of trastuzumab would improve synaptic plasticity there by making refractory schizophrenia amenable to treatment.
SCZ Keywordsschizophrenia, schizophrenic
2J. Neurosci. Res. 2004 Sep 77: 858-66
TitleMicroarray analysis of postmortem temporal cortex from patients with schizophrenia.
AbstractTo examine molecular mechanisms associated with schizophrenia this study measured expression of approximately 12,000 genes in the middle temporal gyrus from 12 subjects with schizophrenia and 14 matched normal controls. Among the most consistent changes in genes with robust expression were significant decreases in the expression of myelination-related genes MAG, PLLP (TM4SF11), PLP1, ERBB3 in subjects with schizophrenia. There was also altered expression of genes regulating neurodevelopment (TRAF4, Neurod1, histone deacetylase 3), a circadian pacemaker (PER1), and several other genes involved in regulation of chromatin function and signaling mechanisms. These findings support the hypothesis that schizophrenia is associated with abnormalities in oligodendroglia and provide initial evidence suggesting a role for epigenetic mechanisms and altered circadian rhythms in this disorder.
SCZ Keywordsschizophrenia, schizophrenic
3Nat. Neurosci. 2004 Jun 7: 575-80
TitleNeuregulin 1-erbB signaling and the molecular/cellular basis of schizophrenia.
Abstractschizophrenia is a devastating psychiatric disease that affects 0.5-1% of the world's adult population. The hypothesis that this disease is a developmental disorder of the nervous system with late onset of its characteristic symptoms has been gaining acceptance in past years. However, the anatomical, cellular and molecular bases of schizophrenia remain unclear. Numerous studies point to alterations in different aspects of brain development as possible causes of schizophrenia, including defects in neuronal migration, neurotransmitter receptor expression and myelination. Recently, the gene that encodes neuregulin-1 (NRG1) has been identified as a potential susceptibility gene for schizophrenia, and defects in the expression of ERBB3, one of the NRG1 receptors, have been shown to occur in the prefrontal cortex of schizophrenic patients, suggesting that NRG1-erbB signaling is involved in the pathogenesis of schizophrenia. These findings open new approaches to defining the molecular and cellular basis of schizophrenia in more mechanistic terms.
SCZ Keywordsschizophrenia, schizophrenic
4Nat. Neurosci. 2004 Jun 7: 575-80
TitleNeuregulin 1-erbB signaling and the molecular/cellular basis of schizophrenia.
Abstractschizophrenia is a devastating psychiatric disease that affects 0.5-1% of the world's adult population. The hypothesis that this disease is a developmental disorder of the nervous system with late onset of its characteristic symptoms has been gaining acceptance in past years. However, the anatomical, cellular and molecular bases of schizophrenia remain unclear. Numerous studies point to alterations in different aspects of brain development as possible causes of schizophrenia, including defects in neuronal migration, neurotransmitter receptor expression and myelination. Recently, the gene that encodes neuregulin-1 (NRG1) has been identified as a potential susceptibility gene for schizophrenia, and defects in the expression of ERBB3, one of the NRG1 receptors, have been shown to occur in the prefrontal cortex of schizophrenic patients, suggesting that NRG1-erbB signaling is involved in the pathogenesis of schizophrenia. These findings open new approaches to defining the molecular and cellular basis of schizophrenia in more mechanistic terms.
SCZ Keywordsschizophrenia, schizophrenic
5Mol. Psychiatry 2005 Mar 10: 309-22
TitleTranscriptional profiling reveals evidence for signaling and oligodendroglial abnormalities in the temporal cortex from patients with major depressive disorder.
AbstractMajor depressive disorder is one of the most common and devastating psychiatric disorders. To identify candidate mechanisms for major depressive disorder, we compared gene expression in the temporal cortex from 12 patients with major depressive disorder and 14 matched controls using Affymetrix HgU95A microarrays. Significant expression changes were revealed in families of genes involved in neurodevelopment, signal transduction and cell communication. Among these, the expression of 17 genes related to oligodendrocyte function was significantly (P < 0.05, fold change > 1.4) decreased in patients with major depressive disorder. Eight of these 17 genes encode structural components of myelin (CNP, MAG, MAL, MOG, MOBP, PMP22, PLLP, PLP1). Five other genes encode enzymes involved in the synthesis of myelin constituents (ASPA, UGT8), or are essential in regulation of myelin formation (ENPP2, EDG2, TF, KLK6). One gene, that is, SOX10, encodes a transcription factor regulating other myelination-related genes. OLIG2 is a transcription factor present exclusively in oligodendrocytes and oligodendrocyte precursors. Another gene, ERBB3, is involved in oligodendrocyte differentiation. In addition to myelination-related genes, there were significant changes in multiple genes involved in axonal growth/synaptic function. These findings suggest that major depressive disorder may be associated with changes in cell communication and signal transduction mechanisms that contribute to abnormalities in oligodendroglia and synaptic function. Taken together with other studies, these findings indicate that major depressive disorder may share common oligodendroglial abnormalities with schizophrenia and bipolar disorder.
SCZ Keywordsschizophrenia, schizophrenic
6Adv Anat Embryol Cell Biol 2007 -1 190: 1-65
TitleThe neuregulin-I/ErbB signaling system in development and disease.
AbstractNeuregulins (NRGs) comprise a large family of EGF-like signaling molecules involved in cell-cell communication during development and disease. The neuregulin family of ligands has four members: NRG1, NRG2, NRG3, and NRG4. Relatively little is known about the biological functions of the NRG2, 3, and 4 proteins. In contrast, the NRG1 proteins have been demonstrated to play important roles during the development of the nervous system, heart, and mammary glands. For example, NRG1 has essential functions in the development of neural crest cells and some of their major derivatives, like Schwann cells and sympathetic neurons. NRG1 controls the trabeculation of the myocardial musculature and the ductal differentiation of the mammary epithelium. Moreover, there is emerging evidence for the involvement of NRG signals in the development and function of several other organ systems, and in human disease, including breast cancer and schizophrenia. Many different isoforms of the Neuregulin-1 gene are synthesized. Such isoforms differ in their tissue-specific expression patterns and their biological activities, thereby contributing to the great diversity of the in vivo functions of NRG1. Neuregulins transmit their signals to target cells by interacting with transmembrane tyrosine kinase receptors of the ErbB family. This family includes four members, the epidermal growth factor receptor (EGF-R, ErbB1, ErbB2, ERBB3, and ErbB4). Receptor-ligand interaction induces the heterodimerization of receptor monomers, which in turn results in the activation of intracellular signaling cascades and the induction of cellular responses including proliferation, migration, differentiation, and survival or apoptosis. In vivo, functional NRG1 receptors are heterodimers composed of ErbB2 with either an ERBB3, or ErbB4 molecule. The tissue-specific distribution of the different receptor types further contributes to the diversity and specificity of the biological functions of this signaling pathway. It is a typical feature of the Neuregulin-1/ErbB signaling pathway to control sequential steps during the development of a particular organ system. For example, this pathway functions in early precursor proliferation, maturation, as well as in the myelination of Schwann cells. The systematic analysis of genetic models that have been established by the help of conventional as well as conditional gene targeting strategies in mice was instrumental for the uncovering of the multitude of biological functions of this signaling system. In this review the basic biology of the Neuregulin-1/ErbB system and how it relates to the in vivo functions were discussed with special emphasis to transgenic techniques in mice.
SCZ Keywordsschizophrenia, schizophrenic
7Brain Res. 2007 Mar 1139: 95-109
TitleWidespread expression of ErbB2, ErbB3 and ErbB4 in non-human primate brain.
AbstractNeuregulin (NRG) signaling proteins interact with ErbB receptors leading to the proliferation, differentiation and migration of neurons and glia in the developing brain. NRG-1/ErbB4 are susceptibility genes for schizophrenia, yet little is known about the neuroanatomical expression of ErbB receptors specifically in primates. We find widespread expression of ErbB2, ERBB3 and ErbB4 receptor mRNAs throughout the telencephalon of juvenile and adult monkeys with in situ hybridization, with ErbB2 and ErbB4 mRNA more abundant than ERBB3 mRNA. ErbB2 and ErbB4 mRNA are expressed at higher levels in grey matter compared to white matter, whereas ERBB3 mRNA is expressed at low levels in both grey and white matter. We also characterized ErbB protein expression with immunoblotting and immunohistochemistry. In frontal cortex, ErbB2, ERBB3 and ErbB4 antibodies immunostained neuronal soma and nuclei. The ErbB2 antibody also immunostained glia at the pial surface. Within white matter, ERBB3 and ErbB4 proteins were localized to putative interstitial white matter neurons while ErbB2 protein was found in glia. Western blotting revealed immunopositive bands at approximately 180-200 kDa for each ErbB, which is consistent with the size of full-length ErbBs. Smaller immunopositive bands were also identified for each ErbB receptor in whole brain homogenates and separate cytoplasmic and nuclear extracts suggesting nuclear ErbB-back-signaling capacity in the brain. The ubiquitous expression of ErbB receptors indicates that many cell populations throughout the brain of juvenile and adult primates have the potential to respond to NRG-1 in a variety of ways.
SCZ Keywordsschizophrenia, schizophrenic
8Neurosci. Res. 2007 Apr 57: 574-8
TitleNo association between the ERBB3 gene and schizophrenia in a Japanese population.
AbstractThere is cumulative evidence that neuregulin 1 (NRG1) is a susceptibility gene for schizophrenia. Postmortem studies on brains from schizophrenia patients have revealed changes in the mRNA expression levels of v-erb-b2 erythroblastic leukemia viral oncogene homolog 3 (ERBB3), one of the NRG1 receptor genes. These observations suggest that NRG1-ERBB signaling is involved in the pathogenesis of schizophrenia. To assess whether the ERBB3 gene could be implicated in vulnerability to schizophrenia, we conducted a case-control (399 patients and 438 controls) association study in Japanese subjects. There were no significant association between the polymorphisms or haplotypes of ERBB3 and schizophrenia. The present study shows that ERBB3 does not play a major role in conferring susceptibility to schizophrenia in the Japanese population.
SCZ Keywordsschizophrenia, schizophrenic
9Schizophr. Res. 2007 Jan 89: 161-4
TitleRGS4 is not a susceptibility gene for schizophrenia in Japanese: association study in a large case-control population.
AbstractThe regulator of the G-protein signaling 4 (RGS4) has been implicated in the susceptibility to schizophrenia. RGS4 interacts with ERBB3 that acts as receptors for neuregulin 1 and these proteins may play a role in the pathogenesis of schizophrenia via glutamatergic dysfunction. Recently, two meta-analysis studies provided different interpretations for the genetic association between RGS4 and schizophrenia. We attempted to confirm this association in a case-control study of 1918 Japanese patients with schizophrenia and 1909 Japanese control subjects. Four widely studied single nucleotide polymorphisms (SNPs) were genotyped, and none showed association with schizophrenia. SNP 1 (rs10917670), p=0.92; SNP 4 (rs951436), p=0.91; SNP 7 (rs951439), p=0.27; and SNP 18 (rs2661319), p=0.43. A haplotype block constructed by these SNPs spans the 5' flanking region to the 5' mid-region of the RGS4 gene. Previous meta-analysis showed that both two major haplotypes of this block were risk haplotypes. The two common haplotypes were observed in the Japanese population. However, neither haplotype was significantly associated with schizophrenia. We conclude that the common haplotypes and SNPs of the RGS4 gene identified thus far are unlikely to contribute to the genetic susceptibility to schizophrenia in the Japanese population.
SCZ Keywordsschizophrenia, schizophrenic
10Am. J. Med. Genet. B Neuropsychiatr. Genet. 2007 Jan 144B: 113-6
TitleSchizophrenia is not associated with the functional candidate gene ERBB3: results from a case-control study.
AbstractIncreasing evidence has supported the hypothesis of a neurodevelopmental component in the etiology of schizophrenia. Recently, several independent microarray gene expression studies have revealed downregulated expression of myelin-related genes in the postmortem brains of schizophrenia patients. Complete myelination of the cortex has been observed to occur in late adolescence and early adulthood, which is typically the age of onset of schizophrenia. ERBB3 is a gene which has not only been found to be downregulated in schizophrenia simultaneously in three microarray studies, but also is a strong candidate because of its potential role in neurodevelopment as a receptor of NRG1. Therefore, we performed association analysis of seven nonsynonymous SNPs in this gene. Two SNPs in ERBB3 (rs773123 and rs2271188) were polymorphic in our samples, neither of which showed significant evidence of association with the illness (P = 0.639 and 0.561, respectively). Because replication across such studies is notoriously difficult, the microarray evidence implicating ERBB3 still strongly supports some role of this gene in schizophrenia. However, our failure to find genetic association suggests that the differential expression of ERBB3 in schizophrenia may be environmentally driven, or involve cis- or trans-acting genetic factors beyond the boundaries of the gene itself.
SCZ Keywordsschizophrenia, schizophrenic
11Int. J. Neuropsychopharmacol. 2008 Jun 11: 553-61
TitleChronic antipsychotic drug administration alters the expression of neuregulin 1beta, ErbB2, ErbB3, and ErbB4 in the rat prefrontal cortex and hippocampus.
AbstractNeuregulin 1 (NRG1) has been identified as a susceptibility gene for schizophrenia, and dysregulation of NRG1 and its ErbB receptors is implicated in the pathophysiology of the disorder. The present study examined the protein expression levels of NRG1beta, ErbB2, ERBB3 and ErbB4 in the rat prefrontal cortex and hippocampus following a 4-wk administration of haloperidol (1 mg/kg i.p.), clozapine (10 mg/kg i.p.), or risperidone (1 mg/kg i.p.) by using immunohistochemistry and Western blot. The results showed that haloperidol promoted the expression of NRG1beta and ErbB4, whereas clozapine inhibited NRG1beta expression in the rat prefrontal cortex. Both haloperidol and clozapine significantly increased the protein levels of NRG1beta and ErbB receptors in the rat hippocampus. Repeated administration of risperidone only increased the expression of NRG1beta and ErbB4 in the hippocampus. Our findings demonstrate that antipsychotic drugs differentially regulate the expression of NRG1 and ErbB receptors in the rat brain, which may provide insight into the molecular basis of the pharmacological profile of antipsychotic drugs.
SCZ Keywordsschizophrenia, schizophrenic
12Mol. Psychiatry 2008 Feb 13: 162-72
TitleMolecular dissection of NRG1-ERBB4 signaling implicates PTPRZ1 as a potential schizophrenia susceptibility gene.
AbstractNeuregulin and the neuregulin receptor ERBB4 have been genetically and functionally implicated in schizophrenia. In this study, we used the yeast two-hybrid system to identify proteins that interact with ERBB4, to identify genes and pathways that might contribute to schizophrenia susceptibility. We identified the MAGI scaffolding proteins as ERBB4-binding proteins. After validating the interaction of MAGI proteins with ERBB4 in mammalian cells, we demonstrated that ERBB4 expression, alone or in combination with ERBB2 or ERBB3, led to the tyrosine phosphorylation of MAGI proteins, and that this could be further enhanced with receptor activation by neuregulin. As MAGI proteins were previously shown to interact with receptor phosphotyrosine phosphatase beta/zeta (RPTPbeta), we postulated that simultaneous binding of MAGI proteins to RPTPbeta and ERBB4 forms a phosphotyrosine kinase/phosphotyrosine phosphatase complex. Studies in cultured cells confirmed both a spatial and functional association between ERBB4, MAGI and RPTPbeta. Given the evidence for this functional association, we examined the genes coding for MAGI and RPTPbeta for genetic association with schizophrenia in a Caucasian United Kingdom case-control cohort (n= approximately 1400). PTPRZ1, which codes for RPTPbeta, showed significant, gene-wide and hypothesis-wide association with schizophrenia in our study (best individual single-nucleotide polymorphism allelic P=0.0003; gene-wide P=0.0064; hypothesis-wide P=0.026). The data provide evidence for a role of PTPRZ1, and for RPTPbeta signaling abnormalities, in the etiology of schizophrenia. Furthermore, the data indicate a role for RPTPbeta in the modulation of ERBB4 signaling that may in turn provide further support for an important role of neuregulin/ERBB4 signaling in the molecular basis of schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic
13Brain Struct Funct 2008 Sep 213: 255-71
TitleAge-related changes in the expression of schizophrenia susceptibility genes in the human prefrontal cortex.
AbstractThe molecular basis of complex neuropsychiatric disorders most likely involves many genes. In recent years, specific genetic variations influencing risk for schizophrenia and other neuropsychiatric disorders have been reported. We have used custom DNA microarrays and qPCR to investigate the expression of putative schizophrenia susceptibility genes and related genes of interest in the normal human brain. Expression of 31 genes was measured in Brodmann's area 10 (BA10) in the prefrontal cortex of 72 postmortem brain samples spanning half a century of human aging (18-67 years), each without history of neuropsychiatric illness, neurological disease, or drug abuse. Examination of expression across age allowed the identification of genes whose expression patterns correlate with age, as well as genes that share common expression patterns and that possibly participate in common cellular mechanisms related to the emergence of schizophrenia in early adult life. The expression of GRM3 and RGS4 decreased across the entire age range surveyed, while that of PRODH and DARPP-32 was shown to increase with age. NRG1, ERBB3, and NGFR show expression changes during the years of greatest risk for the development of schizophrenia. Expression of FEZ1, GAD1, and RGS4 showed especially high correlation with one another, in addition to the strongest mean levels of absolute correlation with all other genes studied here. All microarray data are available at NCBI's Gene Expression Omnibus: GEO Series accession number GSE11546 (http://www.ncbi.nlm.nih.gov/geo) [corrected]
SCZ Keywordsschizophrenia, schizophrenic
14Schizophr Bull 2008 Jan 34: 72-92
TitleDisturbed structural connectivity in schizophrenia primary factor in pathology or epiphenomenon?
AbstractIndirect evidence for disturbed structural connectivity of subcortical fiber tracts in schizophrenia has been obtained from functional neuroimaging and electrophysiologic studies. During the past few years, new structural imaging methods have become available. Diffusion tensor imaging and magnetization transfer imaging (MTI) have been used to investigate directly whether fiber tract abnormalities are indeed present in schizophrenia. To date, findings are inconsistent that may express problems related to methodological issues and sample size. Also, pathological processes detectable with these new techniques are not yet well understood. Nevertheless, with growing evidence of disturbed structural connectivity, myelination has been in the focus of postmortem investigations. Several studies have shown a significant reduction of oligodendroglial cells and ultrastructural alterations of myelin sheats in schizophrenia. There is also growing evidence for abnormal expression of myelin-related genes in schizophrenia: Neuregulin (NRG1) is important for oligodendrocyte development and function, and altered expression of ERBB3, one of the NRG1 receptors, has been shown in schizophrenia patients. This is consistent with recent genetic studies suggesting that NRG1 may contribute to the genetic risk for schizophrenia. In conclusion, there is increasing evidence from multiple sides that structural connectivity might be pathologically changed in schizophrenia illness. Up to the present, however, it has not been possible to decide whether alterations of structural connectivity are intrinsically linked to the primary risk factors for schizophrenia or to secondary downstream effects (ie, degeneration of fibers secondarily caused by cortical neuronal dysfunction)-an issue that needs to be clarified by future research.
SCZ Keywordsschizophrenia, schizophrenic
15Neuroscience 2009 Jun 161: 95-110
TitleIn situ hybridization reveals developmental regulation of ErbB1-4 mRNA expression in mouse midbrain: implication of ErbB receptors for dopaminergic neurons.
AbstractAlthough epidermal growth factor (EGF) and neuregulin-1 are neurotrophic factors for mesencephalic dopaminergic neurons and implicated in schizophrenia, the cellular localization and developmental regulation of their receptors (ErbB1-4) remain to be characterized. Here we investigated the distributions of mRNA for ErbB1-4 in the midbrain of the developing mouse with in situ hybridization and immunohistochemistry. The expression of ErbB1 and ErbB2 mRNAs was relatively high at the perinatal stage and frequently colocalized with mRNA for S100beta and Olig2, markers for immature astrocytes or oligodendrocyte precursors. Modest signal for ErbB1 mRNA was also detected in a subset of dopaminergic neurons. ERBB3 mRNA was detectable at postnatal day 10, peaked at postnatal day 18, and colocalized with 2',3'-cyclic nucleotide 3'-phosphodiesterase, a marker for oligodendrocytes. In contrast, ErbB4 mRNA was exclusively localized in neurons throughout development. Almost all of ErbB4 mRNA-expressing cells (94%-96%) were positive for tyrosine hydroxylase in the substantia nigra pars compacta but 66%-78% in the ventral tegmental area and substantia nigra pars lateralis. Conversely, 92%-99% of tyrosine hydroxylase-positive cells expressed ErbB4 mRNA. The robust and restricted expression of ErbB4 mRNA in the midbrain dopaminergic neurons suggests that ErbB4 ligands, neuregulin-1 and other EGF-related molecules, contribute to development or maintenance of this neuronal population.
SCZ Keywordsschizophrenia, schizophrenic
16World J. Biol. Psychiatry 2009 -1 10: 595-8
TitleCase-control study of association between the functional candidate gene ERBB3 and schizophrenia in Caucasian population.
Abstractschizophrenia is a common psychiatric disorder with a complex genetic aetiology. Evidence shows that the oligodendrocyte and myelin-related genes including ERBB3 are closely related to schizophrenia. Two recent studies (Kanazawa et al. (Am J Med Genet B Neuropsychiatr Genet 2007;144:113)) and Watanabe et al. (Neurosci Res 2007;57:574) reported there was no association between ERBB3 and schizophrenia in Japanese population. We investigated the ERBB3 gene given the putative functional nature of the gene and population heterogeneity between Asian and Caucasian. Scottish case and control samples were sequenced with four SNPs (rs705708 at intron 15, rs2271189, rs773123, rs2271188 at exon 27). We detected rs773123, which is a nonsynonymous Ser/Cys polymorphism located seven bases downstream of rs2271189, with P=0.034. The subgroups of male patients and patients with age at onset <45 showed evidence of significant association with P values of 0.0046 and 0.0055, respectively. To our knowledge, this is the first association study between ERBB3 and schizophrenia in the Caucasian population. Further investigation with large sample size should be helpful to clarify the nature of the gene.
SCZ Keywordsschizophrenia, schizophrenic
17J Neurodev Disord 2009 Dec 1: 302-12
TitleDeficient NRG1-ERBB signaling alters social approach: relevance to genetic mouse models of schizophrenia.
AbstractGrowth factor Neuregulin 1 (NRG1) plays an essential role in development and organization of the cerebral cortex. NRG1 and its receptors, ERBB3 and ERBB4, have been implicated in genetic susceptibility for schizophrenia. Disease symptoms include asociality and altered social interaction. To investigate the role of NRG1-ERBB signaling in social behavior, mice heterozygous for an Nrg1 null allele (Nrg1+/-), and mice with conditional ablation of ERBB3 or Erbb4 in the central nervous system, were evaluated for sociability and social novelty preference in a three-chambered choice task. Results showed that deficiencies in NRG1 or ERBB3 significantly enhanced sociability. All of the mutant groups demonstrated a lack of social novelty preference, in contrast to their respective wild-type controls. Effects of NRG1, ERBB3, or ERBB4 deficiency on social behavior could not be attributed to general changes in anxiety-like behavior, activity, or loss of olfactory ability. Nrg1+/- pups did not exhibit changes in isolation-induced ultrasonic vocalizations, a measure of emotional reactivity. Overall, these findings provide evidence that social behavior is mediated by NRG1-ERBB signaling.
SCZ Keywordsschizophrenia, schizophrenic
18Genet. Mol. Biol. 2009 Oct 32: 729-30
TitleSchizophrenia is not associated with the ERBB3 gene in a Han Chinese population sample: Results from case-control and family-based studies.
AbstractERBB3 (v-erb-b2 erythroblastic leukemia viral oncogene homolog 3), encoding a receptor of neuregulin-1 (NRG1), has been considered a functional candidate gene for schizophrenia susceptibility. In order to investigate a relationship between ERBB3 gene and schizophrenia in the Chinese population, case-control and family-based studies were carried out in 470 cases matched by controls, and in 532 family trios. Our results failed to show any evidence of significant association between the ERBB3 rs2292238 polymorphism and schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic
19Proc. Natl. Acad. Sci. U.S.A. 2010 Mar 107: 5622-7
TitleDisrupted-in-Schizophrenia-1 expression is regulated by beta-site amyloid precursor protein cleaving enzyme-1-neuregulin cascade.
AbstractNeuregulin-1 (NRG1) and Disrupted-in-schizophrenia-1 (DISC1) are promising susceptibility factors for schizophrenia. Both are multifunctional proteins with roles in a variety of neurodevelopmental processes, including progenitor cell proliferation, migration, and differentiation. Here, we provide evidence linking these factors together in a single pathway, which is mediated by ErbB receptors and PI3K/Akt. We show that signaling by NRG1 and NRG2, but not NRG3, increase expression of an isoform of DISC1 in vitro. Receptors ErbB2 and ERBB3, but not ErbB4, are responsible for transducing this effect, and PI3K/Akt signaling is also required. In NRG1 knockout mice, this DISC1 isoform is selectively reduced during neurodevelopment. Furthermore, a similar decrease in DISC1 expression is seen in beta-site amyloid precursor protein cleaving enzyme-1 (BACE1) knockout mice, in which NRG1/Akt signaling is reportedly impaired. In contrast to neuronal DISC1 that was reported and characterized, expression of DISC1 in other types of cells in the brain has not been addressed. Here we demonstrate that DISC1, like NRG and ErbB proteins, is expressed in neurons, astrocytes, oligodendrocytes, microglia, and radial progenitors. These findings may connect NRG1, ErbBs, Akt, and DISC1 in a common pathway, which may regulate neurodevelopment and contribute to susceptibility to schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic
20Am. J. Med. Genet. B Neuropsychiatr. Genet. 2010 Jan 153B: 103-13
TitleIdentification of neuroglycan C and interacting partners as potential susceptibility genes for schizophrenia in a Southern Chinese population.
AbstractChromosome 3p was reported by previous studies as one of the regions showing strong evidence of linkage with schizophrenia. We performed a fine-mapping association study of a 6-Mb high-LD and gene-rich region on 3p in a Southern Chinese sample of 489 schizophrenia patients and 519 controls to search for susceptibility genes. In the initial screen, 4 SNPs out of the 144 tag SNPs genotyped were nominally significant (P < 0.05). One of the most significant SNPs (rs3732530, P = 0.0048) was a non-synonymous SNP in the neuroglycan C (NGC, also known as CSPG5) gene, which belongs to the neuregulin family. The gene prioritization program Endeavor ranked NGC 8th out of the 129 genes in the 6-Mb region and the highest among the genes within the same LD block. Further genotyping of NGC revealed 3 more SNPs to be nominally associated with schizophrenia. Three other genes (NRG1, ERBB3, ErbB4) involved in the neuregulin pathways were subsequently genotyped. Interaction analysis by multifactor dimensionality reduction (MDR) revealed a significant two-SNP interaction between NGC and NRG1 (P = 0.015) and three-SNP interactions between NRG1 and ErbB4 (P = 0.009). The gene NGC is exclusively expressed in the brain. It is implicated in neurodevelopment in rats and was previously shown to promote neurite outgrowth. Methamphetamine, a drug that may induce psychotic symptoms, was reported to alter the expression of NGC. Taken together, these results suggest that NGC may be a novel candidate gene, and neuregulin signaling pathways may play an important role in schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic
21Proc. Natl. Acad. Sci. U.S.A. 2012 Aug 109: 13984-9
TitleDynamically varying interactions between heregulin and ErbB proteins detected by single-molecule analysis in living cells.
AbstractHeregulin (HRG) belongs to the family of EGFs and activates the receptor proteins ERBB3 and ErbB4 in a variety of cell types to regulate cell fate. The interactions between HRG and ERBB3/B4 are important to the pathological mechanisms underlying schizophrenia and some cancers. Here, we observed the reaction kinetics between fluorescently labeled single HRG molecules and ERBB3/B4 on the surfaces of MCF-7 human breast cancer cells. The equilibrium association and the dissociation from equilibrium were also measured using single-molecule imaging techniques. The unitary association processes mirrored the EGF and ErbB1 interactions in HeLa cells [Teramura Y, et al. (2006) EMBO J 25:4215-4222], suggesting that the predimerization of the receptors, followed by intermediate formation (between the first and second ligand-binding events to a receptor dimer), accelerated the formation of doubly liganded signaling dimers of the receptor molecules. However, the dissociation analysis suggested that the first HRG dissociation from the doubly liganded dimer was rapid, but the second dissociation from the singly liganded dimer was slow. The dissociation rate constant from the liganded monomer was intermediate. The dynamic changes in the association and dissociation kinetics in relation to the dimerization of ErbB displayed negative cooperativity, which resulted in apparent low- and high-affinity sites of HRG association on the cell surface.
SCZ Keywordsschizophrenia, schizophrenic
22Hybridoma (Larchmt) 2012 Jun 31: 149-54
TitleTherapeutic use of an anti-ErbB3 monoclonal antibody.
AbstractEmerging evidence suggests that the catalytically inactive ERBB3 (HER3) protein plays a fundamental role in normal tyrosine kinase receptor signaling as well as in aberrant functioning of these signaling pathways, resulting in several forms of human cancers and some mental disorders. Here we report the generation of a specific anti-ERBB3 antibody intended for use in diagnosing disease or therapeutic application. By using the hybridoma technique, one cell line (2E(12)C(3)) stably producing anti-ERBB3 antibody was obtained. Its molecular weight was about 185?kDa and its isotype was IgG 2a and ?, respectively. The affinity constant (Kaff) of the anti-ERBB3 MAb was 5.8310(10) M(-1). This antibody may become a useful tool for diagnostic and therapeutic targeting of ERBB3-expressing cancers or helpful in highlighting the etiology of schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic