Advertisement

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

      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.

      Key Words

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Biological Psychiatry
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Badner J.A.
        • Gershon E.S.
        Meta-analysis of whole-genome linkage scans of bipolar disorder and schizophrenia.
        Mol Psychiatry. 2002; 7: 405-411
        • Bakker S.C.
        • Hoogendoorn M.L.C.
        • Selten J.-P.
        • Verduijn W.
        • Pearson P.L.
        • Sinke R.J.
        • Kahn R.S.
        Neuregulin-1.
        Mol Psychiatry. 2004; 9: 1061-1063
        • Bao J.
        • Lin H.
        • Ouyang Y.
        • Lei D.
        • Osman A.
        • Kim T.-W.
        • et al.
        Activity-dependent transcription regulation of PSD-95 by neuregulin-1 and Eos.
        Nat Neurosci. 2004; 7: 1250-1258
        • Bao J.
        • Wolpowitz D.
        • Role L.W.
        • Talmage D.A.
        Back signaling by the Nrg-1 intracellular domain.
        J Cell Biol. 2003; 161: 1133-1141
        • Beltaifa S.
        • Law A.J.
        • Hyde T.M.
        • McClintock B.
        • Herman M.M.
        • Harrison P.J.
        • et al.
        Expression levels and cellular localization of ErbB receptor mRNAs in the dorsolateral prefrontal cortex in schizophrenia.
        J Neuropathol Exp Neurol. 2005; 64 ([Abstract]): 437
        • Bertram L.
        • Hiltunen M.
        • Parkinson M.
        • Ingelsson M.
        • Lange C.
        • Ramasamy K.
        • et al.
        Family-based associations between Alzheimer’s disease and variants in UBQLN1.
        N Engl J Med. 2005; 352: 884-894
        • Blouin J.L.
        • Dombroski B.A.
        • Nath S.K.
        • Lasseter V.K.
        • Wolyniec P.S.
        • Nestadt G.
        • et al.
        Schizophrenia susceptibility loci on chromosomes 13q32 and 8p21.
        Nat Genet. 1998; 20: 70-73
        • Bray N.J.
        • Preece A.
        • Williams N.M.
        • Moskvina V.
        • Buckland P.R.
        • Owen M.J.
        • O’Donovan M.C.
        Haplotypes at the dystrobrevin binding protein 1 (DTNBP1) gene locus mediate risk for schizophrenia through reduced DTNBP1 expression.
        Hum Mol Genet. 2005; 14: 1947-1954
        • Brzustowicz L.M.
        • Honer W.G.
        • Chow E.W.C.
        • Little D.
        • Hogan J.
        • Hodgkinson K.
        • Bassett A.S.
        Linkage of familial schizophrenia to chromosome 13q32.
        Am J Hum Genet. 1999; 65: 1096-1103
        • Buonanno A.
        • Fischbach G.D.
        Neuregulin and ErbB receptor signaling pathways in the nervous system.
        Curr Opin Neurobiol. 2001; 11: 287-296
        • Burden S.
        • Yarden Y.
        Neuregulins and their receptors.
        Neuron. 1997; 18: 847-855
        • Carpenter G.
        ErbB-4.
        Exp Cell Res. 2003; 284: 66-77
        • Chaudhury A.R.
        • Gerecke K.M.
        • Wyss M.
        • Morgan D.G.
        • Gordon M.N.
        • Carroll S.L.
        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; 62: 42-54
        • Citri A.
        • Skaria K.B.
        • Yarden Y.
        The deaf and the dumb.
        Exp Cell Res. 2003; 284: 54-65
        • Colhoun H.M.
        • McKeigue P.M.
        • Davey Smith G.
        Problems of reporting genetic associations with complex outcomes.
        Lancet. 2003; 361: 865-872
        • Corfas G.
        • Roy K.
        • Buxbaum J.D.
        Neuregulin 1-erbB signaling and the molecular/cellular basis of schizophrenia.
        Nat Neurosci. 2004; 7: 575-580
        • Corvin A.P.
        • Morris D.W.
        • McGhee K.
        • Schwaiger S.
        • Scully P.
        • Quinn J.
        • 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; 9: 208-212
        • Coyle J.T.
        • Tsai G.
        • Goff D.
        Converging evidence of NMDA receptor hypofunction in the pathophysiology of schizophrenia.
        Ann N Y Acad Sci. 2003; 1003: 318-327
        • Craddock N.
        • Owen M.J.
        The beginning of the end for the Kraepelinian dichotomy.
        Br J Psychiatry. 2005; 186: 364-366
        • Crone S.A.
        • Lee K.-F.
        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; 971: 547-553
        • Davis K.L.
        • Stewart D.G.
        • Friedman J.I.
        • Buchsbaum M.
        • Harvey P.D.
        • Hof P.R.
        • et al.
        White matter changes in schizophrenia.
        Arch Gen Psychiatry. 2003; 60: 443-456
        • DeLisi L.E.
        • Shaw S.
        • Crow T.J.
        • Shields G.
        • Smith A.B.
        • Larach V.W.
        • et al.
        Lack of evidence for linkage to chromosomes 13 and 8 for schizophrenia and schizoaffective disorder.
        Am J Med Genet (Neuropsychiat Genet). 2000; 96: 235-239
        • Dempster E.L.
        • Mill J.S.
        • Murray R.
        • Collier D.A.
        Expression analysis of five schizophrenia candidate genes in post-mortem cerebellum samples using quantitative real time PCR.
        Am J Med Genet (Neuropsychiat Genet). 2004; 130B ([abstract]): 146
        • Eastwood S.L.
        • Burnet P.W.J.
        • Harrison P.J.
        Decreased hippocampal expression of the susceptibility gene PPP3CC and other calcineurin subunits in schizophrenia.
        Biol Psychiatry. 2005; 57: 702-710
        • Eilam R.
        • Pinkas-Kramarski R.
        • Ratzkin B.J.
        • Segal M.
        • Yarden Y.
        Activity-dependent regulation of Neu differentiation factor/neuregulin expression in rat brain.
        Proc Natl Acad Sci U S A. 1998; 95: 1888-1893
        • Esper R.M.
        • Loeb J.A.
        Rapid axoglial signaling mediated by neuregulin and neurotrophic factors.
        J Neurosci. 2004; 24: 6218-6227
        • Falls D.L.
        Neuregulins.
        Exp Cell Res. 2003; 284: 14-30
        • Falls D.L.
        Neuregulins and the neuromuscular system.
        J Neurocytol. 2003; 32: 619-647
        • Fischbach G.D.
        • Rosen K.M.
        ARIA.
        Annu Rev Neurosci. 1997; 20: 429-458
        • Flames N.
        • Long J.E.
        • Garratt A.N.
        • Fischer T.M.
        • Gassmann M.
        • Birchmeier C.
        • et al.
        Short- and long-range attraction of cortical GABAergic interneurons by Neuregulin-1.
        Neuron. 2004; 44: 251-261
        • Garcia R.A.
        • Vasudevan K.
        • Buonanno A.
        The neuregulin receptor ErbB-4 interacts with PDZ-containing proteins at neuronal synapses.
        Proc Natl Acad Sci U S A. 2000; 97: 3596-3601
        • Gardner M.
        • Gonzales-Neira A.
        • Lao O.
        • Calafell F.
        • Bertranpetit J.
        • Comas D.
        Extreme population differences across Neuregulin 1 gene, with implications for association studies.
        Mol Psychiatry. 2006; 11: 66-75
        • Gerecke K.M.
        • Wyss J.M.
        • Carroll S.L.
        Neuregulin-1. β induces neurite extension and arborization in cultured hippocampal neurons.
        Mol Cell Neurosci. 2004; 27: 379-393
        • Gierdalski M.
        • Sardi S.P.
        • Corfas G.
        • Juliano S.L.
        Endogenous neuregulin restores radial glia in a (ferret) model of cortical dysplasia.
        J Neurosci. 2005; 25: 8498-8504
        • Go R.C.P.
        • Perry R.T.
        • Weiner H.
        • Bassett S.S.
        • Blacker D.
        • Devlin D.
        • Sweet R.A.
        Neuregulin-1 polymorphism in late onset Alzheimer’s disease families with psychosis.
        Am J Med Genet (Neuropsychiat Genet). 2005; 1398: 28-32
        • Green E.K.
        • Raybould R.
        • Macgregor S.
        • Gordon-Smith K.
        • Heron J.
        • Hyde S.
        • et al.
        Operation of the schizophrenia susceptibility gene, neuregulin 1, across traditional diagnostic boundaries to increase risk for bipolar disorder.
        Arch Gen Psychiatry. 2005; 62: 642-648
        • Gu Z.
        • Jiang Q.
        • Fu A.K.Y.
        • Ip N.Y.
        • Yan Z.
        Regulation of NMDA receptors by neuregulin signaling in prefrontal cortex.
        J Neurosci. 2005; 25: 4974-4984
        • Gurling H.M.D.
        • Kalsi G.
        • Brynjolfson J.
        • Sigmundsson T.
        • Sherrington R.
        • Mankoo B.S.
        • 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; 68: 661-673
        • Hall D.
        • Gogos J.A.
        • Karayiorgou M.
        The contribution of three strong candidate schizophrenia susceptibility genes in demographically distinct populations.
        Genes Brain Behav. 2004; 3: 240-248
        • Harrison P.J.
        The neuropathology of schizophrenia. A critical review of the data and their interpretation.
        Brain. 1999; 122: 593-624
        • Harrison P.J.
        • Owen M.J.
        Genes for schizophrenia? Recent findings and their pathophysiological implications.
        Lancet. 2003; 361: 417-419
        • Harrison P.J.
        • Weinberger D.R.
        Schizophrenia genes, gene expression, and neuropathology.
        Mol Psychiatry. 2005; 10: 40-68
        • Hashimoto R.
        • Straub R.E.
        • Weickert C.S.
        • Hyde T.M.
        • Kleinman J.E.
        • Weinberger D.R.
        Expression analysis of neuregulin-1 in the dorsolateral prefrontal cortex in schizophrenia.
        Mol Psychiatry. 2004; 9: 299-307
        • Holmes W.E.
        • Sliwkowski M.X.
        • Akita R.W.
        • Henzel W.J.
        • Lee J.
        • Park J.W.
        • et al.
        Identification of heregulin, a specific activator of p185erbB2.
        Science. 1992; 256: 1205-1210
        • Hong C.J.
        • Huo S.
        • Liao D.
        • Lee K.
        • Wu H.
        • Tsai S.
        Case-control and family-based association studies between the neuregulin 1 (Arg38Gln) polymorphism and schizophrenia.
        Neurosci Lett. 2004; 366: 158-161
        • Huang Y.Z.
        • Won S.
        • Ali D.W.
        • Wang Q.
        • Tanowitz M.
        • Du Q.S.
        • et al.
        Regulation of neuregulin signaling by PSD-95 interacting with ErbB4 at CNS synapses.
        Neuron. 2000; 26: 443-455
        • Iwata N.
        • Suzuki T.
        • Ikeda M.
        • Kitajima T.
        • Yamanouchi Y.
        • Inada T.
        • Ozaki N.
        No association with the neuregulin 1 haplotype to Japanese schizophrenia.
        Mol Psychiatry. 2004; 9: 126-127
        • Kampman O.
        • Anttila S.
        • Ari I.
        • Saarela M.
        • Rontu R.
        • Mattila K.M.
        • et al.
        Neuregulin genotype and medication response in Finnish patients with schizophrenia.
        Neuroreport. 2004; 15: 2517-2520
        • Kaufmann C.A.
        • Suarez B.
        • Malaspina D.
        • Pepple J.
        • Svrakic D.
        • Markel P.D.
        • et al.
        NIMH Genetics Initiative Millennium Schizophrenia Consortium. Linkage analysis of African-American pedigrees.
        Am J Med Genet. 1998; 81: 282-289
        • Kendler K.S.
        • MacLean C.J.
        • O’Neill F.A.
        • Burke J.
        • Murphy B.
        • Duke F.
        • et al.
        Evidence for a schizophrenia vulnerability locus on chromosome 8p in the Irish study of high-density schizophrenia families.
        Am J Psychiatry. 1996; 153: 1534-1540
        • Kerber G.
        • Streif R.
        • Schwaiger F.
        • Kreutzberg G.
        • Hager G.
        Neuregulin-1 isoforms are differentially expressed in the intact and regenerating adult rat nervous system.
        J Mol Neurosci. 2003; 21: 149-165
        • Kunugi H.
        • Curtis D.
        • Valalda H.P.
        • Nanko S.
        • Powell J.F.
        • Murray R.M.
        • et al.
        A linkage study of schizophrenia with DNA markers from chromosome 8p21-22 in 25 multiplex families.
        Schizophr Res. 1996; 22: 61-68
        • Kwon O.-B.
        • Longart M.
        • Vulhorst D.
        • Hoffman D.A.
        • Buonanno A.
        Neuregulin-1 reverses long-term potentiation at CA1 hippocampal synapses.
        J Neurosci. 2005; 12: 9378-9383
        • Lachman H.
        • Pedrosa E.
        • Ye K.
        • Nolan K.
        • Saito T.
        Analysis of polymorphisms in AT-rich domains of neuregulin 1 gene in schizophrenia.
        Am J Med Genet (Neuropsychiat Genet). 2005; 138B ([Abstract]): 87
        • Lai C.
        • Feng L.Y.
        Neuregulin induces proliferation of neural progenitor cells via PLC/PKC pathway.
        Biochem Biophys Res Commun. 2004; 319: 603-611
        • Law A.J.
        • Weickert C.S.
        • Hyde T.M.
        • Kleinman J.E.
        • Harrison P.J.
        Neuregulin-1 (NRG-1) mRNA and protein in the adult human brain.
        Neuroscience. 2004; 127: 125-136
        • Law A.J.
        • Weickert C.S.
        • Hyde T.
        • Kleinman J.E.
        • Harrison P.J.
        Alterations of neuregulin 1 and ErbB4 expression in the cerebellum in schizophrenia.
        Schizophr Bull 31. 2005; ([Abstract]): 114241
        • Leonard S.
        • Mexal S.
        • Berger R.
        • Freedman R.
        Neuregulin-1 expression is decreased in primary skin fibroblasts of schizophrenic subjects.
        Schizophr Bull 31. 2005; ([Abstract]): 114870
        • Levinson D.F.
        • Wildenauer D.B.
        • Schwab S.G.
        • Albus M.
        • Hallmayer J.
        • Lerer B.
        • et al.
        Additional support for schizophrenia linkage on chromosomes 6 and 8.
        Am J Med Genet. 1996; 67: 580-594
        • Lewis C.M.
        • Levinson D.F.
        • Wise L.H.
        • DeLisi L.E.
        • Straub R.E.
        • Hovatta I.
        • et al.
        Genome scan meta-analysis of schizophrenia and bipolar disorder, part II.
        Am J Hum Genet. 2003; 73: 34-48
        • Lewis D.A.
        • Hashimoto T.
        • Volk D.W.
        Cortical inhibitory neurons and schizophrenia.
        Nature Rev Neurosci. 2005; 6: 312-324
        • Li Q.
        • Loeb J.A.
        Neuregulin-heparan-sulfate proteoglycan interactions produce sustained erbB receptor activation required for the induction of acetylcholine receptors in muscle.
        J Biol Chem. 2001; 276: 38068-38075
        • Li T.
        • Stefansson H.
        • Gudfinnsson E.
        • Cai G.
        • Liu X.
        • Murray R.M.
        • et al.
        Identification of a novel neuregulin 1 at-risk haplotype in Han schizophrenia Chinese patients, but no association with Icelandic/Scottish risk haplotype.
        Mol Psychiatry. 2004; 9: 698-705
        • Lin H.-F.
        • Liu Y.-L.
        • Liu C.-M.
        • Hung S.-I.
        • Hwu H.-G.
        • Chen W.I.
        Neuregulin 1 gene and variations in perceptual aberration of schizotypal personality in adolescents.
        Psychol Med. 2005; 35: 1589-1598
        • Liu C.M.
        • Hwu H.G.
        • Fann C.
        • Lin C.Y.
        • Liu Y.L.
        • Ou-Yang W.C.
        • et al.
        Linkage evidence of schizophrenia to loci near neuregulin 1 gene n chromosome 8p21 in Taiwanese families.
        Am J Med Genet (Neuropsychiat Genet). 2005; 134B: 79-83
        • Loeb J.A.
        Neuregulin.
        J Neurocytol. 2003; 32: 649-664
        • Mata I.
        • Arranz M.J.
        • Staddon S.
        • Beperet M.
        • Lopez-Ilundain J.M.
        • Murray R.M.
        • Kerwin R.W.
        Association study of neuregulin 1 gene and schizophrenia in a population isolate from northern Spain.
        Am J Med Genet (Neuropsychiat Genet). 2004; 130B ([Abstract]): 83
        • Meng Y.
        • Zhang Y.
        • Tregoubov V.
        • Falls D.L.
        • Jia Z.
        Regulation of spine morphology and synaptic function by LIMK and the actin cytoskeleton.
        Rev Neurosci. 2003; 14: 233-240
        • Meyer D.
        • Yammai T.
        • Garratt A.
        • Riethmacher-Sonnenberg E.
        • Kane D.
        • Theill L.E.
        • et al.
        Isoform-specific expression and function of neuregulin.
        Development. 1997; 124: 3575-3586
        • Michailov G.V.
        • Sereda M.W.
        • Brinkmann B.G.
        • Fischer T.M.
        • Haug B.
        • Birchmeier C.
        • et al.
        Axonal neuregulin-1 regulates myelin sheath thickness.
        Science. 2004; 304: 700-703
        • Mirnics K.
        • Middleton F.A.
        • Stanwood G.D.
        • Lewis D.A.
        • Levitt P.
        Disease-specific changes in regulator of G-protein signaling 4 (RGS4) expression in schizophrenia.
        Mol Psychiatry. 2001; 6: 293-301
        • Murphy S.
        • Krainock R.
        • Tham M.
        Neuregulin signaling via erbB receptor assemblies in the nervous system.
        Mol Neurobiol. 2002; 25: 67-77
        • Navon R.
        • Shamir E.
        • Zerah G.
        • Swartz M.
        • Kaganovich M.
        • Korostishevsky M.
        Association and expression analysis of neuregulin-1 region.
        Am J Med Genet (Neuropsychiat Genet). 2004; 130B ([abstract]): 86
        • Norton N.
        • Moskvina V.
        • Morris D.W.
        • Bray N.J.
        • Zammit S.
        • et al.
        Evidence that interaction between Neuregulin 1 and its receptor erbB4 increases susceptibility to schizophrenia.
        Am J Med Genet (Neuropsychiat Genet). 2006; 144B: 96-101
        • Owen M.J.
        • Craddock N.
        • O’Donovan M.C.
        Schizophrenia.
        Trends Genetics. 2005; 21: 519-525
        • Ozaki M.
        Neuregulins and the shaping of synapses.
        The Neuroscientist. 2001; 7: 146-154
        • Ozaki M.
        • Itoh K.
        • Miyakawa Y.
        • Kishida H.
        • Hashikawa T.
        Protein processing and releases of neuregulin-1 are regulated in an activity-dependent manner.
        J Neurochem. 2004; 91: 176-188
        • Paige G.P.
        • George V.
        • Go R.C.
        • Page P.Z.
        • Allison D.B.
        “Are we there yet?”.
        Am J Hum Genet. 2003; 73: 711-719
        • Petryshen T.L.
        • Middelton F.A.
        • Kirby A.
        • Aldinger K.A.
        • Purcell S.
        • Tahl A.R.
        • et al.
        Support for involvement of neuregulin 1 in schizophrenia pathophysiology.
        Mol Psychiatry. 2005; 10: 366-374
        • Pulver A.E.
        • Lasseter V.K.
        • Kasch L.
        • Wolyniec P.
        • Nestadt G.
        • Blouin J.-L.
        • et al.
        Schizophrenia.
        Am J Med Genet. 1995; 60: 252-260
        • Roysommuti S.
        • Carroll S.L.
        • Wyss J.M.
        Neuregulin-1β modulates in vivo entorhinal-hippocampal synaptic transmission in adult rats.
        Neuroscience. 2003; 121: 779-785
        • Schmid R.S.
        • McGrath B.
        • Berechid B.E.
        • Boyles B.
        • Marchionni M.
        • Sestan N.
        • Anton E.S.
        Neuregulin 1-erbB2 signaling is required for the establishment of radial glia and their transformation into astrocytes in cerebral cortex.
        Proc Natl Acad Sci U S A. 2003; 100: 4251-4256
        • Shaw S.H.
        • Kelly M.
        • Smith A.B.
        • Shields G.
        • Hopkins P.J.
        • Loftus J.
        • et al.
        A genome-wide search for schizophrenia susceptibility genes.
        Am J Med Genet. 1998; 81: 364-376
        • Shyu W.-C.
        • Lin S.-Z.
        • Chiang M.-F.
        • Yang H.-I.
        • Thajeb P.
        • Li H.
        Neuregulin-1 reduces ischaemia-induced brain damage in rats.
        Neurobiol Aging. 2004; 25: 935-944
        • Silberberg G.
        • Navon R.
        The involvement of ErbB4 with schizophrenia.
        Am J Hum Genet Neuropscyhiatr Genet. 2005; 138B ([Abstract]): 130
        • Singleton A.
        • Myers A.
        • Hardy J.
        The law of mass action applied to neurodegnerative disease.
        Hum Mol Genet. 2004; 13: R123-R126
        • Sklar P.
        • Pato M.T.
        • Kirby A.
        • Petryshen T.L.
        • Medeiros H.
        • Carvalho C.
        • et al.
        Genome-wide scan in Portugese Island families identifies 5q31-5q35 as a susceptibility locus for schizophrenia and psychosis.
        Mol Psychiatry. 2004; 9: 213-218
        • Stefansson H.
        • Sarginson J.
        • Kong A.
        • Yates P.
        • Steinthorsdottir V.
        • Gudfinnsson E.
        • et al.
        Association of neuregulin 1 with schizophrenia confirmed in a Scottish population.
        Am J Hum Genet. 2003; 72: 83-87
        • Stefansson H.
        • Sigurdsson E.
        • Steinthorsdottir V.
        • Bjornsdottir S.
        • Sigmundsson T.
        • Ghosh S.
        • et al.
        Neuregulin 1 and susceptibility to schizophrenia.
        Am J Hum Genet. 2002; 71: 877-892
        • Steinthorsdottir V.
        • Stefansson H.
        • Ghosh S.
        • Birgisdottir B.
        • Bjornsdottir S.
        • Fasquel A.C.
        • et al.
        Multiple novel transcription initiation sites for NRG1.
        Gene. 2004; 342: 97-105
        • Tang J.X.
        • Chen W.Y.
        • He G.
        • Zhou J.
        • Gu N.F.
        • Feng G.Y.
        • He L.
        Polymorphisms within 5′ end of the Neuregulin 1 gene are genetically associated with schizophrenia in the Chinese population.
        Mol Psychiatry. 2004; 9: 11-12
        • Taveggia C.
        • Zanazzi G.
        • Petrylak A.
        • Yano H.
        • Rosenbluth J.
        • Einheber S.
        • et al.
        Neuregulin-1 Type III determines the ensheathment fate of axons.
        Neuron. 2005; 47: 681-694
        • Thiselton D.L.
        • Webb B.T.
        • Neale B.M.
        • Ribble R.
        • O’Neill F.A.
        • Walsh D.
        • et al.
        No evidence for linkage or association of neuregulin-1 (NRG1) with disease in the Irish study of high-density schizophrenia families (ISHDSF).
        Mol Psychiatry. 2004; 9: 777-783
        • Tkachev D.
        • Mimmack M.
        • Ryan M.M.
        • Wayland M.
        • Freeman T.
        • Jones P.B.
        • et al.
        Oligodendrocyte dysfunction in schizophrenia and bipolar disorder.
        Lancet. 2003; 362: 798-805
        • Tosato S.
        • Dazzan P.
        • Collier D.
        Association between the neuregulin 1 gene and schizophrenia.
        Schizophr Bull. 2005; 31: 613-617
        • Tunbridge E.M.
        • Harrison P.J.
        • Weinberger D.R.
        Catechol-o-methyltransferase, cognition and schizophrenia.
        Biol Psychiatry. 2006; (XX:XX–XX)
        • Wang J.Y.
        • Miller S.J.
        • Falls D.L.
        The N-terminal region of neuregulin isoforms determines the accumulation of cell surface and released neuregulin ectodomain.
        J Biol Chem. 2001; 276: 2841-2851
        • Weickert C.S.
        • Straub R.E.
        • McClintock B.W.
        • Matsumoto M.
        • Hashimoto M.
        • Hyde T.M.
        • et al.
        Human dysbindin (DTNBP1) gene expression in normal brain and in schizophrenic prefrontal cortex and midbrain.
        Arch Gen Psychiatry. 2004; 61: 544-555
        • Williams N.M.
        • Norton N.
        • Williams H.
        • Ekholm B.
        • Hamshere M.L.
        • Lindblom Y.
        • et al.
        A systematic genomewide linkage study in 353 sib pairs with schizophrenia.
        Am J Hum Genet. 2003; 73: 1355-1367
        • Williams N.M.
        • Preece A.
        • Spurlock G.
        • Norton N.
        • Williams H.J.
        • Zammit S.
        • et al.
        Support for genetic variation in neuregulin 1 and susceptibility to schizophrenia.
        Mol Psychiatry. 2003; 8: 485-487
        • Yang J.Z.
        • Si T.M.
        • Ruan Y.
        • Ling Y.S.
        • Han Y.H.
        • Wang X.L.
        • et al.
        Association study of neuregulin 1 gene with schizophrenia.
        Mol Psychiatry. 2003; 8: 706-709
        • Yarden Y.
        • Sliwkowski M.X.
        Untangling the ErbB signaling network.
        Nature Rev Mol Cell Biol. 2001; 2: 127-137
        • Zhao X.
        • Shi Y.
        • Tang J.
        • Tang R.
        • Yu L.
        • Gu N.
        • et al.
        A case control and family based association study of the neuregulin1 gene and schizophrenia.
        J Med Genet. 2004; 41: 31-34