Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Neuregulin1-induced cell migration is impaired in schizophrenia: association with neuregulin1 and catechol-o-methyltransferase gene polymorphisms

Molecular Psychiatry volume 12, pages 946–957 (2007)Cite this article

Abstract

Neuregulin1 (NRG1), a candidate susceptibility gene for schizophrenia, plays a critical role in neuronal migration and central nervous system development. However, its relation to schizophrenia pathogenesis is unknown. Here we show that B lymphoblasts migrate to NRG1 through the ErbB-signaling system as observed in neuronal cells. We assessed NRG1-induced cell migration in B lymphoblasts from patients with schizophrenia and found that NRG1-induced migration is significantly decreased compared with control individuals in two independent cohorts. This impaired migration is related at least in part to reduced AKT phosphorylation in the patients. Moreover, the magnitude of NRG1-induced migration is associated with polymorphisms of the NRG1 and catechol-o-methyltransferase genes and with an epistatic interaction of these genes. This study demonstrates that the migratory response of schizophrenia-derived cells to NRG1 is impaired and is associated with genetic variations in more than one schizophrenia susceptibility gene, providing a novel insight into potential neurodevelopmental mechanisms of schizophrenia.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6

Similar content being viewed by others

References

  1. Pulver AE, Lasseter VK, Kasch L, Wolyniec P, Nestadt G, Blouin JL et al. Schizophrenia: a genome scan targets chromosomes 3p and 8p as potential sites of susceptibility genes. Am J Med Genet 1995; 60: 252–260.

    Article  CAS  Google Scholar 

  2. Kendler KS, MacLean CJ, O'Neill FA, 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.

    Article  CAS  Google Scholar 

  3. Kaufmann CA, Suarez B, Malaspina D, Pepple J, Svrakic D, Markel PD et al. NIMH Genetics Initiative Millenium Schizophrenia Consortium: linkage analysis of African-American pedigrees. Am J Med Genet 1998; 81: 282–289.

    Article  CAS  Google Scholar 

  4. Blouin JL, Dombroski BA, Nath SK, Lasseter VK, Wolyniec PS, Nestadt G et al. Schizophrenia susceptibility loci on chromosomes 13q32 and 8p21. Nat Genet 1998; 20: 70–73.

    Article  CAS  Google Scholar 

  5. Shaw SH, Kelly M, Smith AB, Shields G, Hopkins PJ, Loftus J et al. A genome-wide search for schizophrenia susceptibility genes. Am J Med Genet 1998; 81: 364–376.

    Article  CAS  Google Scholar 

  6. Brzustowicz LM, Honer WG, Chow EW, Little D, Hogan J, Hodgkinson K et al. Linkage of familial schizophrenia to chromosome 13q32. Am J Hum Genet 1999; 65: 1096–1103.

    Article  CAS  Google Scholar 

  7. Badner JA, Gershon ES . Meta-analysis of whole-genome linkage scans of bipolar disorder and schizophrenia. Mol Psychiatry 2002; 7: 405–411.

    Article  CAS  Google Scholar 

  8. Lewis CM, Levinson DF, Wise LH, DeLisi LE, Straub RE, Hovatta I et al. Genome scan meta-analysis of schizophrenia and bipolar disorder, part II: Schizophrenia. Am J Hum Genet 2003; 73: 34–48.

    Article  CAS  Google Scholar 

  9. 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.

    Article  Google Scholar 

  10. 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.

    Article  CAS  Google Scholar 

  11. Williams NM, Preece A, Spurlock G, Norton N, Williams HJ, Zammit S et al. Support for genetic variation in neuregulin 1 and susceptibility to schizophrenia. Mol Psychiatry 2003; 8: 485–487.

    Article  CAS  Google Scholar 

  12. Law AJ, Weickert CS, Hyde TM, Kleinman JE, Harrison PJ . Neuregulin-1 (NRG-1) mRNA and protein in the adult human brain. Neuroscience 2004; 127: 125–136.

    Article  CAS  Google Scholar 

  13. Hashimoto R, Straub RE, Weickert CS, Hyde TM, Kleinman JE, Weinberger DR . Expression analysis of neuregulin-1 in the dorsolateral prefrontal cortex in schizophrenia. Mol Psychiatry 2004; 9: 299–307.

    Article  CAS  Google Scholar 

  14. Aston C, Jiang L, Sokolov BP . Microarray analysis of postmortem temporal cortex from patients with schizophrenia. J Neurosci Res 2004; 77: 858–866.

    Article  CAS  Google Scholar 

  15. Rimer M, Barrett DW, Maldonado MA, Vock VM, Gonzalez-Lima F . Neuregulin-1 immunoglobulin-like domain mutant mice: clozapine sensitivity and impaired latent inhibition. NeuroReport 2005; 16: 271–275.

    Article  CAS  Google Scholar 

  16. Gerlai R, Pisacane P, Erickson S . Heregulin, but not ErbB2 or ErbB3, heterozygous mutant mice exhibit hyperactivity in multiple behavioral tasks. Behav Brain Res 2000; 109: 219–227.

    Article  CAS  Google Scholar 

  17. Huang YZ, Won S, Ali DW, Wang Q, Tanowitz M, Du QS et al. Regulation of neuregulin signaling by PSD-95 interacting with ErbB4 at CNS synapses. Neuron 2000; 26: 443–455.

    Article  CAS  Google Scholar 

  18. Kwon OB, Longart M, Vullhorst D, Hoffman DA, Buonanno A . Neuregulin-1 reverses long-term potentiation at CA1 hippocampal synapses. J Neurosci 2005; 25: 9378–9383.

    Article  CAS  Google Scholar 

  19. Ozaki M, Sasner M, Yano R, Lu HS, Buonanno A . Neuregulin-beta induces expression of an NMDA-receptor subunit. Nature 1997; 390: 691–694.

    Article  CAS  Google Scholar 

  20. Gu Z, Jiang Q, Fu AK, Ip NY, Yan Z . Regulation of NMDA receptors by neuregulin signaling in prefrontal cortex. J Neurosci 2005; 25: 4974–4984.

    Article  CAS  Google Scholar 

  21. Rieff HI, Raetzman LT, Sapp DW, Yeh HH, Siegel RE, Corfas G . Neuregulin induces GABA(A) receptor subunit expression and neurite outgrowth in cerebellar granule cells. J Neurosci 1999; 19: 10757–10766.

    Article  CAS  Google Scholar 

  22. Okada M, Corfas G . Neuregulin1 downregulates postsynaptic GABAA receptors at the hippocampal inhibitory synapse. Hippocampus 2004; 14: 337–344.

    Article  CAS  Google Scholar 

  23. Liu Y, Ford B, Mann MA, Fischbach GD . Neuregulins increase alpha7 nicotinic acetylcholine receptors and enhance excitatory synaptic transmission in GABAergic interneurons of the hippocampus. J Neurosci 2001; 21: 5660–5669.

    Article  CAS  Google Scholar 

  24. Harrison PJ, Weinberger DR . Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence. Mol Psychiatry 2005; 10: 40–68.

    Article  CAS  Google Scholar 

  25. Corfas G, Roy K, Buxbaum JD . Neuregulin 1–ErbB signaling and the molecular/cellular basis of schizophrenia. Nat Neurosci 2004; 7: 575–580.

    Article  CAS  Google Scholar 

  26. Anton ES, Marchionni MA, Lee KF, Rakic P . Role of GGF/neuregulin signaling in interactions between migrating neurons and radial glia in the developing cerebral cortex. Development 1997; 124: 3501–3510.

    CAS  PubMed  Google Scholar 

  27. Rio C, Rieff HI, Qi P, Khurana TS, Corfas G . Neuregulin and erbB receptors play a critical role in neuronal migration. Neuron 1997; 19: 39–50.

    Article  CAS  Google Scholar 

  28. Flames N, Long JE, Garratt AN, Fischer TM, Gassmann M, Birchmeier C et al. Short- and long-range attraction of cortical GABAergic interneurons by neuregulin-1. Neuron 2004; 44: 251–261.

    Article  CAS  Google Scholar 

  29. Lopez-Bendito G, Cautinat A, Sanchez JA, Bielle F, Flames N, Garratt AN et al. Tangential neuronal migration controls axon guidance: a role for neuregulin-1 in thalamocortical axon navigation. Cell 2006; 125: 127–142.

    Article  CAS  Google Scholar 

  30. Calaora V, Rogister B, Bismuth K, Murray K, Brandt H, Leprince P et al. Neuregulin signaling regulates neural precursor growth and the generation of oligodendrocytes in vitro. J Neurosci 2001; 21: 4740–4751.

    Article  CAS  Google Scholar 

  31. Sussman CR, Vartanian T, Miller RH . The ErbB4 neuregulin receptor mediates suppression of oligodendrocyte maturation. J Neurosci 2005; 25: 5757–5762.

    Article  CAS  Google Scholar 

  32. Colognato H, Ramachandrappa S, Olsen IM, ffrench-Constant C . Integrins direct Src family kinases to regulate distinct phases of oligodendrocyte development. J Cell Biol 2004; 167: 365–375.

    Article  CAS  Google Scholar 

  33. Kim JY, Sun Q, Oglesbee M, Yoon SO . The role of ErbB2 signaling in the onset of terminal differentiation of oligodendrocytes in vivo. J Neurosci 2003; 23: 5561–5571.

    Article  CAS  Google Scholar 

  34. Weinberger DR, Marenco S . Schizophrenia as a neurodevelopmental disorder. In: Hirsch S, Weinberger DR (eds). Schizophrenia. Blackwell Science: Oxford, UK, 2003, pp 326–348.

    Chapter  Google Scholar 

  35. Wu JY, Feng L, Park HT, Havlioglu N, Wen L, Tang H et al. The neuronal repellent Slit inhibits leukocyte chemotaxis induced by chemotactic factors. Nature 2004; 410: 948–952.

    Article  Google Scholar 

  36. Ma Q, Jones D, Borghesani PR, Segal RA, Nagasawa T, Kishimoto T et al. Impaired B-lymphopoiesis, myelopoiesis, and derailed cerebellar neuron migration in CXCR4- and SDF-1-deficient mice. Proc Natl Acad Sci USA 1998; 95: 9448–9453.

    Article  CAS  Google Scholar 

  37. Zou YR, Kottmann AH, Kuroda M, Taniuchi I, Littman DR . Function of the chemokine receptor CXCR4 in haematopoiesis and in cerebellar development. Nature 1998; 393: 595–599.

    Article  CAS  Google Scholar 

  38. Weinberger DR . Implications of normal brain development for the pathogenesis of schizophrenia. Arch Gen Psychiatry 1987; 44: 660–669.

    Article  CAS  Google Scholar 

  39. Egan MF, Goldberg TE, Gscheidle T, Weirich M, Bigelow LB, Weinberger DR . Relative risk of attention deficits in siblings of patients with schizophrenia. Am J Psychiatry 2000; 157: 1309–1316.

    Article  CAS  Google Scholar 

  40. Pressman S, Rotter JI . Epstein–Barr virus transformation of cryopreserved lymphocytes: prolonged experience with technique. Am J Hum Genet 1991; 49: 467.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Kato S, Kobayashi T, Yamada K, Nishii K, Sawada H, Ishiguro H et al. Expression of erbB receptors mRNA in thyroid tissues. Biochim Biophys Acta 2004; 1673: 194–200.

    Article  CAS  Google Scholar 

  42. Kriebel PW, Barr VA, Parent CA . Adenylyl cyclase localization regulates streaming during chemotaxis. Cell 2003; 112: 549–560.

    Article  CAS  Google Scholar 

  43. Marmor MD, Skaria KB, Yarden Y . Signal transduction and oncogenesis by ErbB/HER receptors. Int J Radiat Oncol Biol Phys 2004; 58: 903–913.

    Article  CAS  Google Scholar 

  44. Law AJ, Lipska BK, Weickert CS, Hyde TM, Straub RE, Hashimoto R et al. Neuregulin 1 transcripts are differentially expressed in schizophrenia and regulated by 5′ SNPs associated with the disease. Proc Natl Acad Sci USA 2005; 103: 6747–6752.

    Article  Google Scholar 

  45. Matsui A, Ikeda T, Enomoto K, Nakashima H, Omae K, Watanabe M et al. Progression of human breast cancers to the metastatic state is linked to genotypes of catechol-O-methyltransferase. Cancer Lett 2000; 150: 23–31.

    Article  CAS  Google Scholar 

  46. Leone F, Perissinotto E, Cavalloni G, Fonsato V, Bruno S, Surrenti N et al. Expression of the c-ErbB-2/HER2 proto-oncogene in normal hematopoietic cells. J Leukoc Biol 2003; 74: 593–601.

    Article  CAS  Google Scholar 

  47. Roy-Burman P, Devi BG, Parker JW . Differential expression of c-erbB, c-myc and c-myb oncogene loci in human lymphomas and leukemias. Int J Cancer 1983; 32: 185–191.

    Article  CAS  Google Scholar 

  48. Buhring HJ, Sures I, Jallal B, Weiss FU, Busch FW, Ludwig WD et al. The receptor tyrosine kinase p185HER2 is expressed on a subset of B-lymphoid blasts from patients with acute lymphoblastic leukemia and chronic myelogenous leukemia. Blood 1995; 86: 1916–1923.

    CAS  PubMed  Google Scholar 

  49. Mahtouk K, Hose D, Reme T, De Vos J, Jourdan M, Moreaux J et al. Expression of EGF-family receptors and amphiregulin in multiple myeloma. Amphiregulin is a growth factor for myeloma cells. Oncogene 2005; 24: 3512–3524.

    Article  CAS  Google Scholar 

  50. Graus-Porta D, Beerli RR, Daly JM, Hynes NE . ErbB-2, the preferred heterodimerization partner of all ErbB receptors, is a mediator of lateral signaling. EMBO J 1997; 16: 1647–1655.

    Article  CAS  Google Scholar 

  51. Buonanno A, Fischbach GD . Neuregulin and ErbB receptor signaling pathways in the nervous system. Curr Opin Neurobiol 2001; 11: 287–296.

    Article  CAS  Google Scholar 

  52. Falls DL . Neuregulins: functions, forms, and signaling strategies. Exp Cell Res 2003; 284: 14–30.

    Article  CAS  Google Scholar 

  53. Emamian ES, Hall D, Birnbaum MJ, Karayiorgou M, Gogos JA . Convergent evidence for impaired AKT1–GSK3beta signaling in schizophrenia. Nat Genet 2004; 36: 131–137.

    Article  CAS  Google Scholar 

  54. Li Q, Ahmed S, Loeb JA . Development of an autocrine neuregulin signaling loop with malignant transformation of human breast epithelial cells. Cancer Res 2004; 64: 7078–7085.

    Article  CAS  Google Scholar 

  55. Bao J, Wolpowitz D, Role LW, Talmage DA . Back signaling by the Nrg-1 intracellular domain. J Cell Biol 2003; 161: 1133–1141.

    Article  CAS  Google Scholar 

  56. Egan MF, Goldberg TE, Kolachana BS, Callicott JH, Mazzanti CM, Straub RE et al. Effect of COMT Val108/158 Met genotype on frontal lobe function and risk for schizophrenia. Proc Natl Acad Sci USA 2001; 98: 6917–6922.

    Article  CAS  Google Scholar 

  57. Chen J, Lipska BK, Halim N, Ma QD, Matsumoto M, Melhem S et al. Functional analysis of genetic variation in catechol-O-methyltransferase (COMT): effects on mRNA, protein, and enzyme activity in postmortem human brain. Am J Hum Genet 2004; 75: 807–821.

    Article  CAS  Google Scholar 

  58. Harrison PJ . The neuropathology of schizophrenia. A critical review of the data and their interpretation. Brain 1999; 122: 593–624.

    Article  Google Scholar 

Download references

Acknowledgements

This research was supported by the Intramural Research Program of the National Institute of Mental Health, NIH. We thank Drs SP Markey and DL Murphy, NIMH, for their generous support, Drs CA Combs at the National Heart, Lung, and Blood Institute and C Smith at the National Institute of Neurological Disorders and Stroke for assistance with confocal microscopy, and DJ Venzon of the National Cancer Institute for statistical consultation and advice. We also thank Drs JW Daly of the National Institute of Diabetes and Digestive and Kidney Diseases, L Neckers of the National Cancer Institute and B Lu of the National Institute of Child Health and Human Development or scientific advice and critical review of the manuscript.

Author information

Author notes

  1. Y Sei and R Ren-Patterson: These authors contributed equally to this work.

Authors and Affiliations

  1. Clinical Brain Disorder Branch, Genes, Cognition, and Psychosis Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA

    Y Sei, R Ren-Patterson, Z Li, M F Egan, B S Kolachana & D R Weinberger

  2. Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford, UK

    E M Tunbridge

Authors
  1. Y Sei
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. R Ren-Patterson
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Z Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. E M Tunbridge
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. M F Egan
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. B S Kolachana
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. D R Weinberger
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Y Sei or D R Weinberger.

Additional information

Supplementary Information accompanies the paper on the Molecular Psychiatry website (http://www.nature.com/mp)

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sei, Y., Ren-Patterson, R., Li, Z. et al. Neuregulin1-induced cell migration is impaired in schizophrenia: association with neuregulin1 and catechol-o-methyltransferase gene polymorphisms. Mol Psychiatry 12, 946–957 (2007). https://doi.org/10.1038/sj.mp.4001994

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.mp.4001994

Keywords

This article is cited by

Search

Advanced search

Quick links