Neuregulin 1 and Schizophrenia: Genetics, Gene Expression, and Neurobiology

Harrison, Paul J.; Law, Amanda J.

doi:10.1016/j.biopsych.2005.11.002

Cited by 427 publications

(335 citation statements)

References 95 publications

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“…While NRG1 is one of the most established risk genes for schizophrenia in association studies, its functional role is unclear [3,13,19].…”

mentioning

confidence: 99%

“…Thus, as there is no overall increase in general activity in COMT mutants, disruption of exploration and habituation may involve a schizophrenia-related disruption of DAdependent working memory. Conversely, NRG1 is involved in distinct processes, including CNS development, synapse formation, neuronal migration and synaptic plasticity, that are thought to be dysfunctional in schizophrenia [3,13]. It is increasingly recognised that schizophrenia is influenced by several genes of small effect, including COMT and NRG1.…”

mentioning

confidence: 99%

“…It is increasingly recognised that schizophrenia is influenced by several genes of small effect, including COMT and NRG1. However, none are clearly associated with a specific schizophrenia endophenotype [5,9,12,13,18,19,27].…”

mentioning

confidence: 99%

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Exploratory and habituation phenotype of heterozygous and homozygous COMT knockout mice

Babovic

O’Tuathaigh

O’Sullivan

et al. 2007

Behavioural Brain Research

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“…While NRG1 is one of the most established risk genes for schizophrenia in association studies, its functional role is unclear [3,13,19].…”

mentioning

confidence: 99%

mentioning

confidence: 99%

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Exploratory and habituation phenotype of heterozygous and homozygous COMT knockout mice

Babovic

O’Tuathaigh

O’Sullivan

et al. 2007

Behavioural Brain Research

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“…It is unclear therefore how NRG4 is inserted into the membrane and how the ectodomain is shed (as is the case for some NRG1 isoforms, Wakatsuki et al, 2004) to produce an ErbB4 receptoractivating ligand. Harari et al (1999) who reported the first sequence of NRG4 showed that a refolded peptide representing the EGF domain of mouse NRG4 stimulated the phosphorylation of HER4 and the downstream second messenger protein mitogen-activated protein kinase.Extensive alternative mRNA splicing and the use of at least six sites of initiation of transcription in NRG1 allows the production of more than 15 variants (Harrison and Law, 2006). NRG2 is also alternatively spliced to produce a and b variants (Yamada et al, 2000), and recently isoforms of NRG3 have been described (Carteron et al, 2006).…”

mentioning

confidence: 99%

“…Extensive alternative mRNA splicing and the use of at least six sites of initiation of transcription in NRG1 allows the production of more than 15 variants (Harrison and Law, 2006). NRG2 is also alternatively spliced to produce a and b variants (Yamada et al, 2000), and recently isoforms of NRG3 have been described (Carteron et al, 2006).…”

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confidence: 99%

Characterization of the cell membrane-associated products of the Neuregulin 4 gene

et al. 2007

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The NRG4 gene is a member of a family of four genes that encode a class of epidermal growth factors. This gene has been reported to express a protein designated here as NRG4A1. We describe here a novel splice variant of the NRG4 gene, NRG4A2, which encodes a C-terminal region containing a predicted type I PDZ-binding peptide. Both NRG4A1 and NRG4A2 were shown to be expressed on the cell surface, as expected by the presence of a predicted transmembrane sequence, and were modified at a single N-linked glycosylation site in the extracellular domain. Significant stabilization of expression of both proteins was seen in the presence of the proteosome inhibitor MG-132 suggesting that they are normally degraded by this system. N-terminal cleavage was inhibited in both isotypes by the broad-spectrum matrix metalloproteinase inhibitor, galardin (GM 6001). A glycosylated, secreted form of NRG4A1 was detected in the cell medium which showed biological activity in two assays, phosphorylation of the HER4 receptor and stimulation of neurite formation in PC-12 cells stably expressing HER4. Transfection and expression of green fluorescent protein-tagged proteins and immunofluorescent staining with specific anti-peptide antibodies showed that NRG4A1 is localized to membrane ruffles, while NRG4A2 has a more punctate membrane distribution.Oncogene ( The neuregulins (NRGs) are a family of growth factors that possess a wide range of possible activities including promoting cell growth, differentiation, migration, apoptosis and adhesion (Falls, 2003). There are four mammalian NRG genes (NRG1-4) each of which can encode a homologous epidermal growth factor (EGF)-like domain which is the minimum requirement for the stimulation of ErbB receptor tyrosine kinases. NRGs 1 and 2 interact with ErbB3 and ErbB4, while NRG3 and NRG4 are reported to bind only ErbB4 (Hobbs et al., 2002). Each NRG gene has a characteristic pattern of expression in normal tissues, NRG1-3 are all expressed in the nervous system, while NRG4 was detected in a limited number of adult tissues but not the brain (Harari et al., 1999). To date, only one product has been reported for the NRG4 gene which encodes a 115 amino acid transmembrane protein containing an EGF domain homologous to the other NRGs, but outside this region shares little sequence homology with the other NRGs (Buonanno and Fishbach, 2001). It is probable that NRG4 is synthesized as a pro-form, similar to other ErbB ligands, with which it shares structural similarity. Hydropathy plot analysis predicts a single transmembrane region between amino acids 64 and 83 and sequence analysis predicts an EGF domain at the immediate N terminus of the protein (Harari et al., 1999) which contains a single N-linked glycosylation site (NYT) located at residue 39 between the fifth and sixth cysteine, a feature found at the N terminus of the EGF domain of NRG2 (Higashiyama et al., 1997) but not in any of the other EGF receptor ligands. This is followed by a relatively short serine-rich region, representing a putative proteoly...

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A Population-Based Study of Shared Genetic Variation Between Premorbid IQ and Psychosis Among Male Twin Pairs and Sibling Pairs From Sweden

Fowler

Zammit²,

Rasmussen³

2012

Arch Gen Psychiatry

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Using IQ as a phenotype to identify genes that have an important role in the genetic origin of schizophrenia is unlikely to be a successful strategy. The low correlation seen in this study between premorbid IQ and psychosis vs the higher correlations reported in the literature with postmorbid IQ suggests the correlation between these phenotypes has more to do with the influence that the onset of psychosis has on cognitive functioning than with shared genetic origin.

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Neuregulin 1 and Schizophrenia: Genetics, Gene Expression, and Neurobiology

Cited by 427 publications

References 95 publications

Exploratory and habituation phenotype of heterozygous and homozygous COMT knockout mice

Exploratory and habituation phenotype of heterozygous and homozygous COMT knockout mice

Characterization of the cell membrane-associated products of the Neuregulin 4 gene

A Population-Based Study of Shared Genetic Variation Between Premorbid IQ and Psychosis Among Male Twin Pairs and Sibling Pairs From Sweden

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