Elsevier

Biological Psychiatry

Volume 60, Issue 2, 15 July 2006, Pages 132-140
Biological Psychiatry

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

https://doi.org/10.1016/j.biopsych.2005.11.002Get rights and content

Neuregulin 1 (NRG1) is a leading schizophrenia susceptibility gene. The NRG1 locus on chromosome 8p shows linkage to the disorder, and genetic association has been found between schizophrenia and various non-coding polymorphisms and haplotypes, especially at the 5′ end of the NRG1 gene, in many but not all case-control and family studies. NRG1 is a pleiotropic growth factor, important in nervous system development and functioning; roles include the modulation of neuronal migration, synaptogenesis, gliogenesis, neuron-glia communication, myelination, and neurotransmission. Understanding the neurobiology of NRG1 and its involvement in schizophrenia is challenged by the complexity of the gene, which gives rise to multiple functionally distinct isoforms, including six “types” of NRG1 defined by 5′ exon usage. Type IV and type I NRG1 may be particularly relevant to schizophrenia, with initial data showing altered expression of these isoforms in the disorder or in association with NRG1 risk alleles. We review the structure and functions of NRG1, consider the evidence for and against it being a schizophrenia susceptibility gene, and discuss mechanisms that might underlie the contribution of NRG1 to disease pathophysiology.

Section snippets

The NRG1 Gene and Its Isoforms

The human NRG1 gene is located at chromosome 8p13. It spans approximately 1.4 megabases, has more than 20 exons and several large introns (Figure 1), and gives rise to at least 15 isoforms. All isoforms contain a core EGF domain, EGFc, encoded by exon E130, but other elements of the protein are variable. (In the absence of an agreed or definitive exon numbering system for NRG1, exons are labeled as described by Steinthorsdottir et al [2004], with the number denoting their length in nucleotides;

The 8p Locus

Chromosome 8p, especially a 30cM region around 8p21.1-22, has been implicated as a locus harboring one or more schizophrenia genes by several linkage studies (Blouin et al 1998, Brzustowicz et al 1999, Gurling et al 2001, Kendler et al 1996, Levinson et al 1996, Liu et al 2005, Pulver et al 1995, Stefansson et al 2002). As with all other putative schizophrenia loci, there have also been equivocal and negative findings (DeLisi et al 2000, Kaufmann et al 1998, Kunugi et al 1996, Shaw et al 1998,

Neuregulin 1 Expression and Function in Schizophrenia

As noted earlier, an alteration in NRG1 expression, and thence NRG1 function, is the putative molecular mechanism mediating the influence of NRG1 upon schizophrenia risk. Recent data provide initial experimental support for, and refinement of, this possibility (Table 4).

Hashimoto et al (2004) studied types I–III NRG1 transcripts in the dorsolateral prefrontal cortex and found increased type I NRG1 mRNA in schizophrenia. The elevation was present relative to the other NRG1 isoforms and to three

Summary

There is now substantial but not incontrovertible evidence that genetic variation in NRG1 is associated with schizophrenia (Table 3). Proving this beyond all reasonable doubt will be intrinsically difficult, for two main reasons—which apply not only to NRG1 but to other putative susceptibility genes for psychiatric disorders (Colhoun et al 2003, Harrison and Weinberger 2005, Paige et al 2003). The first reason relates to the genetic architecture. Schizophrenia is a complex genetic disorder with

References (103)

  • H.M.D. Gurling et al.

    Genomewide genetic linkage analysis confirms the presence of susceptibility loci for schizophrenia on chromosomes 1q32.2, 5q33.2, and 8p21-22 and provides support for linkage to schizophrenia on chromosomes 11q23.3-24 and 20q12.1-11.23

    Am J Hum Genet

    (2001)
  • P.J. Harrison et al.

    Genes for schizophrenia? Recent findings and their pathophysiological implications

    Lancet

    (2003)
  • C.J. Hong et al.

    Case-control and family-based association studies between the neuregulin 1 (Arg38Gln) polymorphism and schizophrenia

    Neurosci Lett

    (2004)
  • Y.Z. Huang et al.

    Regulation of neuregulin signaling by PSD-95 interacting with ErbB4 at CNS synapses

    Neuron

    (2000)
  • H. Kunugi et al.

    A linkage study of schizophrenia with DNA markers from chromosome 8p21-22 in 25 multiplex families

    Schizophr Res

    (1996)
  • C. Lai et al.

    Neuregulin induces proliferation of neural progenitor cells via PLC/PKC pathway

    Biochem Biophys Res Commun

    (2004)
  • A.J. Law et al.

    Neuregulin-1 (NRG-1) mRNA and protein in the adult human brain

    Neuroscience

    (2004)
  • C.M. Lewis et al.

    Genome scan meta-analysis of schizophrenia and bipolar disorder, part IISchizophrenia

    Am J Hum Genet

    (2003)
  • Q. Li et al.

    Neuregulin-heparan-sulfate proteoglycan interactions produce sustained erbB receptor activation required for the induction of acetylcholine receptors in muscle

    J Biol Chem

    (2001)
  • S. Roysommuti et al.

    Neuregulin-1β modulates in vivo entorhinal-hippocampal synaptic transmission in adult rats

    Neuroscience

    (2003)
  • W.-C. Shyu et al.

    Neuregulin-1 reduces ischaemia-induced brain damage in rats

    Neurobiol Aging

    (2004)
  • H. Stefansson et al.

    Association of neuregulin 1 with schizophrenia confirmed in a Scottish population

    Am J Hum Genet

    (2003)
  • H. Stefansson et al.

    Neuregulin 1 and susceptibility to schizophrenia

    Am J Hum Genet

    (2002)
  • V. Steinthorsdottir et al.

    Multiple novel transcription initiation sites for NRG1

    Gene

    (2004)
  • C. Taveggia et al.

    Neuregulin-1 Type III determines the ensheathment fate of axons

    Neuron

    (2005)
  • D. Tkachev et al.

    Oligodendrocyte dysfunction in schizophrenia and bipolar disorder

    Lancet

    (2003)
  • J.Y. Wang et al.

    The N-terminal region of neuregulin isoforms determines the accumulation of cell surface and released neuregulin ectodomain

    J Biol Chem

    (2001)
  • N.M. Williams et al.

    A systematic genomewide linkage study in 353 sib pairs with schizophrenia

    Am J Hum Genet

    (2003)
  • J.A. Badner et al.

    Meta-analysis of whole-genome linkage scans of bipolar disorder and schizophrenia

    Mol Psychiatry

    (2002)
  • S.C. Bakker et al.

    Neuregulin-1Genetic support for schizophrenia subtypes

    Mol Psychiatry

    (2004)
  • J. Bao et al.

    Activity-dependent transcription regulation of PSD-95 by neuregulin-1 and Eos

    Nat Neurosci

    (2004)
  • J. Bao et al.

    Back signaling by the Nrg-1 intracellular domain

    J Cell Biol

    (2003)
  • S. Beltaifa et al.

    Expression levels and cellular localization of ErbB receptor mRNAs in the dorsolateral prefrontal cortex in schizophrenia

    J Neuropathol Exp Neurol

    (2005)
  • L. Bertram et al.

    Family-based associations between Alzheimer’s disease and variants in UBQLN1

    N Engl J Med

    (2005)
  • J.L. Blouin et al.

    Schizophrenia susceptibility loci on chromosomes 13q32 and 8p21

    Nat Genet

    (1998)
  • N.J. Bray et al.

    Haplotypes at the dystrobrevin binding protein 1 (DTNBP1) gene locus mediate risk for schizophrenia through reduced DTNBP1 expression

    Hum Mol Genet

    (2005)
  • A.R. Chaudhury et al.

    Neuregulin-1 and ErbB4 immunoreactivity is associated with neuritic plaques in Alzheimer disease brain and in a transgenic model of Alzheimer disease

    J Neuropathol Exp Neurol

    (2003)
  • G. Corfas et al.

    Neuregulin 1-erbB signaling and the molecular/cellular basis of schizophrenia

    Nat Neurosci

    (2004)
  • A.P. Corvin et al.

    Confirmation and refinement of an “at-risk” haplotype for schizophrenia suggests the EST cluster, Hs.97362, as a potential susceptibility gene at the Neuregulin-1 locus

    Mol Psychiatry

    (2004)
  • J.T. Coyle et al.

    Converging evidence of NMDA receptor hypofunction in the pathophysiology of schizophrenia

    Ann N Y Acad Sci

    (2003)
  • N. Craddock et al.

    The beginning of the end for the Kraepelinian dichotomy

    Br J Psychiatry

    (2005)
  • S.A. Crone et al.

    Gene targeting reveals multiple essential functions of the neuregulin signaling system during development of the neuroendocrine and nervous systems

    Ann N Y Acad Sci

    (2002)
  • K.L. Davis et al.

    White matter changes in schizophreniaEvidence for myelin-related dysfunction

    Arch Gen Psychiatry

    (2003)
  • L.E. DeLisi et al.

    Lack of evidence for linkage to chromosomes 13 and 8 for schizophrenia and schizoaffective disorder

    Am J Med Genet (Neuropsychiat Genet)

    (2000)
  • E.L. Dempster et al.

    Expression analysis of five schizophrenia candidate genes in post-mortem cerebellum samples using quantitative real time PCR

    Am J Med Genet (Neuropsychiat Genet)

    (2004)
  • R. Eilam et al.

    Activity-dependent regulation of Neu differentiation factor/neuregulin expression in rat brain

    Proc Natl Acad Sci U S A

    (1998)
  • R.M. Esper et al.

    Rapid axoglial signaling mediated by neuregulin and neurotrophic factors

    J Neurosci

    (2004)
  • D.L. Falls

    Neuregulins and the neuromuscular system10 years of answers and questions

    J Neurocytol

    (2003)
  • G.D. Fischbach et al.

    ARIAA neuromuscular junction neuregulin

    Annu Rev Neurosci

    (1997)
  • R.A. Garcia et al.

    The neuregulin receptor ErbB-4 interacts with PDZ-containing proteins at neuronal synapses

    Proc Natl Acad Sci U S A

    (2000)
  • Cited by (387)

    • Cannabis effects on the adolescent brain

      2022, Cannabis and the Developing Brain
    View all citing articles on Scopus
    View full text