Neuregulin 1 transcripts are differentially expressed in schizophrenia and regulated by 5′ SNPs associated with the disease

Law, Amanda J.; Lipska, Barbara K.; Weickert, Cynthia Shannon; Hyde, Thomas M.; Straub, Richard E.; Hashimoto, Ryota; Harrison, Paul J.; Kleinman, Joel E.; Weinberger, Daniel R.

doi:10.1073/pnas.0602002103

Cited by 374 publications

(231 citation statements)

References 46 publications

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“…In particular, altered NRG1 expression, rather than loss of function, has been associated with this disease (54). Consistent with this finding, a number of groups have observed altered expression patterns for various NRG1 isoforms (54 -56).…”

Section: Discussionsupporting

confidence: 65%

ErbB4-Neuregulin Signaling Modulates Synapse Development and Dendritic Arborization through Distinct Mechanisms

Krivosheya

Tapia

Levinson

et al. 2008

Journal of Biological Chemistry

102

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Perturbations in neuregulin-1 (NRG1)/ErbB4 function have been associated with schizophrenia. Affected patients exhibit altered levels of these proteins and display hypofunction of glutamatergic synapses as well as altered neuronal circuitry. However, the role of NRG1/ErbB4 in regulating synapse maturation and neuronal process formation has not been extensively examined. Here we demonstrate that ErbB4 is expressed in inhibitory interneurons at both excitatory and inhibitory postsynaptic sites. Overexpression of ErbB4 postsynaptically enhances size but not number of presynaptic inputs. Conversely, knockdown of ErbB4 using shRNA decreases the size of presynaptic inputs, demonstrating a specific role for endogenous ErbB4 in synapse maturation. Using ErbB4 mutant constructs, we demonstrate that ErbB4-mediated synapse maturation requires its extracellular domain, whereas its tyrosine kinase activity is dispensable for this process. We also demonstrate that depletion of ErbB4 decreases the number of primary neurites and that stimulation of ErbB4 using a soluble form of NRG1 results in exuberant dendritic arborization through activation of the tyrosine kinase domain of ErbB4 and the phosphoinositide 3-kinase pathway. These findings demonstrate that NRG1/ErbB4 signaling differentially regulates synapse maturation and dendritic morphology via two distinct mechanisms involving trans-synaptic signaling and tyrosine kinase activity, respectively.Although central nervous system synapses utilize a variety of brain-specific molecules to mediate contact formation and maturation, some of the proteins implicated in this process are also major players in neuromuscular junction development. Among these shared molecules are NRG1 3 and its receptor, ErbB4, which are expressed in both the developing and adult brain. Neuregulins comprise a family of four related genes (nrg1-4), each producing a large number of isoforms via differential promoter usage and alternative splicing (1, 2). NRGs contain EGF-like repeats, which enable them to bind to and activate EGF family receptors (ErbB2-4). Previous studies showed that NRG1 is initially synthesized as a transmembrane protein, which then undergoes proteolytic processing, whereby the extracellular EGF-containing fragment is released into the extracellular environment. The remaining intracellular fragment has been shown to translocate into the nucleus, where it regulates neuronal survival and transcription of PSD-95 (3, 4). Proteolytic processing of NRG1 is also regulated by neuronal activity and by interaction with ErbB receptors (3, 5). NRG1 is widely expressed throughout development and adulthood, with the highest expression in nervous tissue (6) and is essential for survival. In the central nervous system NRG1 is also required for differentiation, migration, and development of neurons and glia as well as for axonal myelination and pathfinding, dendritic development, and neurotransmitter receptor maintenance. During development, NRG1-ErbB signaling mediates radial glia maintenance and elonga...

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Section: Discussionsupporting

confidence: 65%

ErbB4-Neuregulin Signaling Modulates Synapse Development and Dendritic Arborization through Distinct Mechanisms

Krivosheya

Tapia

Levinson

et al. 2008

Journal of Biological Chemistry

102

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“…Hashimoto et al (12) examined type I-III NRG1 transcripts in the dorsolateral prefrontal cortex and found increased NRG1 type I mRNA in schizophrenia, a finding that was subsequently confirmed in a separate and larger sample in the hippocampus (10). However, evidence for a relationship between genetic risk in the gene and increased expression of type I mRNA in the brain was inconclusive.…”

Section: Neuregulin 1 (Nrg1)mentioning

confidence: 97%

“…The association with schizophrenia was first reported in an Icelandic population in which a NRG1 haplotype (Hap ice ) consisting of five single nucleotide polymorphisms (SNPs) and two microsatellites covering the 5Ј-end of the gene doubled the risk for the disorder (9). Four of these SNPs (SNP8NRG221132, SNP8NRG221533, SNP8NRG241930, and SNP8NRG243177 (rs6994992)) represent a 22-kb surrogate haplotype that resides in the 5Ј flanking putative promoter region of NRG1 directly upstream of the novel E187 exon, which is unique to the NRG1 type IV isoform (7,10). Follow-up studies in multiple ethnic populations and a meta-analysis have confirmed genetic association between schizophrenia and NRG1 using markers within the same core haplotype (8,11) or with overlapping markers in the 5Ј region, making NRG1 a leading schizophrenia susceptibility gene.…”

Section: Neuregulin 1 (Nrg1)mentioning

confidence: 99%

Molecular Cloning of a Brain-specific, Developmentally Regulated Neuregulin 1 (NRG1) Isoform and Identification of a Functional Promoter Variant Associated with Schizophrenia

Tan

Wang

Gold

et al. 2007

Journal of Biological Chemistry

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140

113

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Neuregulin 1 (NRG1) is essential for the development and function of multiple organ systems, and its dysregulation has been linked to diseases such as cancer and schizophrenia. Recently, altered expression of a novel isoform (type IV) in the brain has been associated with schizophrenia-related genetic variants, especially rs6994992 (SNP8NRG243177). Here we have isolated and characterized full-length NRG1 type IV cDNAs from the adult and fetal human brain and identified novel splice variants of NRG1. Full-length type IV spans 1.8 kb and encodes a putative protein of 590 amino acids with a predicted molecular mass of ϳ66 kDa. The transcript consists of 11 exons with an Ig-like domain, an epidermal growth factor-like (EGF) domain, a ␤-stalk, a transmembrane domain, and a cytoplasmic "a-tail," placing it in the ␤1a NRG1 subclass. NRG1 type IV was not detected in any tissues except brain and a putative type IV NRG1 protein of 66 kDa was similarly brain-specific. Type IV transcripts are more abundantly expressed in the fetal brain, where, in addition to the full-length structure, two novel type IV variants were identified. In vitro luciferase-reporter assays demonstrate that the 5 promoter region upstream of type IV is functional, with differential activity associated with genetic variation at rs6994992, and that promoter competition may impact on type IV expression. Our data suggest that type IV is a unique brain-specific NRG1 that is differentially expressed and processed during early development, is translated, and its expression regulated by a schizophrenia risk-associated functional promoter or single nucleotide polymorphism (SNP).

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“…Our results indicate that loss of NRG1-erbB signaling in OLs may contribute to these diseases. Thus, the possibility that the reported increases in NRG1 or erbB4 expression (4,5,34,35) or erbB4 activation (36) reflect a compensatory response to a loss/reduction in function in this signaling pathway needs to be considered. This signaling pathway may also contribute to neuropsychiatric disorders through nongenetic mechanisms because both NRG1 and erbB4 expression have been shown to be altered by environmental insults (37)(38)(39).…”

Section: Discussionmentioning

confidence: 99%

Loss of erbB signaling in oligodendrocytes alters myelin and dopaminergic function, a potential mechanism for neuropsychiatric disorders

Roy

Murtie

El-Khodor

et al. 2007

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

290

243

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Several psychiatric disorders are associated with white matter defects, suggesting that oligodendrocyte (OL) abnormalities underlie some aspects of these diseases. Neuregulin 1 (NRG1) and its receptor, erbB4, are genetically linked with susceptibility to schizophrenia and bipolar disorder. In vitro studies suggest that NRG1-erbB signaling is important for OL development. To test whether erbB signaling contributes to psychiatric disorders by regulating the structure or function of OLs, we analyzed transgenic mice in which erbB signaling is blocked in OLs in vivo. Here we show that loss of erbB signaling leads to changes in OL number and morphology, reduced myelin thickness, and slower conduction velocity in CNS axons. Furthermore, these transgenic mice have increased levels of dopamine receptors and transporters and behavioral alterations consistent with neuropsychiatric disorders. These results indicate that defects in white matter can cause alterations in dopaminergic function and behavior relevant to neuropsychiatric disorders.dopamine ͉ erbB receptor ͉ neuregulin ͉ schizophrenia ͉ white matter N euregulin 1 (NRG1), a growth factor essential for brain development, and erbB4, one of its receptors, are genetically linked to schizophrenia and bipolar disorder (1-4). A role for NRG1-erbB receptor signaling in psychiatric diseases is also supported by studies showing that expression levels or function of NRG1, erbB3, and erbB4 are altered in patient tissues (1,4,5). Moreover, mice with reduced levels of NRG1 or erbB4 exhibit behavioral alterations relevant to mental illness (6-9). Although the evidence linking this pathway and psychiatric disorders is strong, the mechanisms by which it contributes to these diseases remain unknown. NRG1-erbB signaling is important in neurons, astrocytes, and oligodendrocytes (OLs), but the specific cell types through which altered NRG1-erbB signaling contributes to these disorders is undefined.Significant alterations in white matter are found in schizophrenia, bipolar disorder, major depression, anxiety, and obsessivecompulsive disorder (10-14), and genes expressed by OLs have been linked with some of these diseases (15, 16). Interestingly, NRG1-erbB signaling regulates OL development in vitro (17), although this has not been shown in the intact organism.To determine whether erbB signaling plays a role in CNS myelination and whether disruption of this pathway in OLs produces defects related to human psychiatric disorders, we analyzed mice in which erbB signaling in OLs is blocked by expression of a dominant negative erbB receptor (DN-erbB4) (18). We show that alterations in erbB signaling lead to changes in OL morphology, number, and function in vivo. Moreover, these transgenic (Tg) mice have increased levels of functional dopamine transporters (DAT) and D1 receptors and exhibit behavioral alterations suggestive of neuropsychiatric disorders. Together, these results indicate that altered NRG1-erbB signaling in OLs may be a potential contributor to the pathogenesis of mental illness....

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Neuregulin 1 transcripts are differentially expressed in schizophrenia and regulated by 5′ SNPs associated with the disease

Cited by 374 publications

References 46 publications

ErbB4-Neuregulin Signaling Modulates Synapse Development and Dendritic Arborization through Distinct Mechanisms

ErbB4-Neuregulin Signaling Modulates Synapse Development and Dendritic Arborization through Distinct Mechanisms

Molecular Cloning of a Brain-specific, Developmentally Regulated Neuregulin 1 (NRG1) Isoform and Identification of a Functional Promoter Variant Associated with Schizophrenia

Loss of erbB signaling in oligodendrocytes alters myelin and dopaminergic function, a potential mechanism for neuropsychiatric disorders

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