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 Research Article
  • Published:

Expression of disrupted in schizophrenia 1 (DISC1) protein in the adult and developing mouse brain indicates its role in neurodevelopment

Abstract

Disrupted in Schizophrenia 1 (DISC1) was identified as a potential susceptibility gene for schizophrenia due to its disruption by a balanced t(1;11) (q42;q14) translocation, which has been shown to cosegregate with major psychiatric disease in a large Scottish family. We have recently presented evidence that DISC1 exists in a neurodevelopmentally regulated protein complex with Nudel. In this study, we report the protein expression profile of DISC1 in the adult and developing mouse brain utilizing immunohistochemistry and quantitative Western blot. In the adult mouse brain, DISC1 is expressed in neurons within various brain areas including the olfactory bulb, cortex, hippocampus, hypothalamus, cerebellum and brain stem. During development, DISC1 protein is detected at all stages, from E10 to 6 months old, with two significant peaks of protein expression of a DISC1 isoform at E13.5 and P35. Interestingly, these time points correspond to critical stages during mouse development, the active neurogenesis period in the developing brain and the period of puberty. Together, these results suggest that DISC1 may play a critical role in brain development, consistent with the neurodevelopmental hypothesis of the etiology of schizophrenia.

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

Access options

Buy this article

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

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7

Similar content being viewed by others

References

  1. Stevens JR . Schizophrenia: reproductive hormones and the brain. Am J Psychiatry 2002; 159: 713–719.

    Article  Google Scholar 

  2. Harrison PJ . Schizophrenia: a disorder of neurodevelopment? Curr Opin Neurobiol 1997; 7: 285–289.

    Article  CAS  Google Scholar 

  3. Lewis DA, Levitt P . Schizophrenia as a disorder of neurodevelopment. Annu Rev Neurosci 2002; 25: 409–432.

    Article  CAS  Google Scholar 

  4. Weinberger DR, Torrey EF, Neophytides AN, Wyatt RJ . Lateral cerebral ventricular enlargement in chronic schizophrenia. Arch Gen Psychiatry 1979; 36: 735–739.

    Article  CAS  Google Scholar 

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

    Article  Google Scholar 

  6. Lafargue T, Brasic J . Neurodevelopmental hypthesis of schizophrenia: a central sensory disturbance. Med Hypotheses 2000; 55: 314–318.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  8. Millar JK, Wilson-Annan JC, Anderson S, Christie S, Taylor MS, Semple CA et al. Disruption of two novel genes by a translocation co-segregating with schizophrenia. Hum Mol Genet 2000; 9: 1415–1423.

    Article  CAS  Google Scholar 

  9. Ekelund J, Hovatta I, Parker A, Paunio T, Varilo T, Martin R et al. Chromosome 1 loci in Finnish schizophrenia families. Hum Mol Genet 2001; 10: 1611–1617.

    Article  CAS  Google Scholar 

  10. Hennah W, Varilo T, Kestilä M, Paunio T, Arajärvi JH, Haukka J et al. Haplotype transmission analysis provides evidence of association for DISC1 to schizophrenia and suggests sex-dependent effects. Hum Mol Genetics 2003; 12: 13151–13159.

    Article  Google Scholar 

  11. Hwu HG, Liu CM, Fann CS, Ou-Yang WC, Lee SF . Linkage of schizophrenia with chromosome 1q loci in Taiwanese families. Mol Psychiatry 2003; 8: 445–452.

    Article  CAS  Google Scholar 

  12. Brandon NJ, Handford EJ, Schurov I, Rain J-C, Pelling M, Duran-Jimeniz B et al. Disrupted in Schizophrenia1 and Nudel form a neurodevelopmentally regulated protein complex: implications for schizophrenia and other major neurological disorders. Mol Cell Neurosci 2004; 25: 42–55.

    Article  CAS  Google Scholar 

  13. Dobyns WB, Reiner O, Carrozzo R, Ledbetter DH . Lissencephaly: a human brain malformation associated with deletion of the LIS1 gene located at chromosome 17p13. J Am Med Assoc 1993; 270: 2838–2842.

    Article  CAS  Google Scholar 

  14. Feng Y, Olson EC, Stukenberg PT, Flanagan LA, Kirschner MW, Walsh CA . LIS1 regulates CNS lamination by interacting with mNudE, a central component of the centrosome. Neuron 2000; 28: 665–679.

    Article  CAS  Google Scholar 

  15. Efimov VP, Morris NR . The LIS1-related NUDF protein of Aspergillus nidulans interacts with the coiled-coil domain of the NUDE/RO11 protein. J Cell Biol 2000; 150: 681–688.

    Article  CAS  Google Scholar 

  16. Efimov VP . Roles of NUDE and NUDF proteins of Aspergillus nidulans: insights from intracellular localization and overexpression effects. Mol Biol Cell 2003; 14: 871–888.

    Article  CAS  Google Scholar 

  17. Niethammer M, Smith DS, Ayala R, Peng J, Ko J, Lee MS et al. NUDEL is a novel Cdk5 substrate that associates with LIS1 and cytoplasmic dynein. Neuron 2000; 28: 697–711.

    Article  CAS  Google Scholar 

  18. Sasaki S, Shionoya A, Ishida M, Gambello MJ, Yingling J, Wynshaw-Boris A et al. A LIS1/NUDEL/cytoplasmic dynein heavy chain complex in the developing and adult nervous system. Neuron 2000; 28: 681–696.

    Article  CAS  Google Scholar 

  19. Sweeney KJ, Prokscha A, Eichele G . NudE-L, a novel Lis1-interacting protein, belongs to a family of vertebrate coiled-coil proteins. Mech Dev 2001; 101: 21–33.

    Article  CAS  Google Scholar 

  20. Ross ME, Walsh CA . Human brain malformations and their lessons for neuronal migration. Annu Rev Neurosci 2001; 24: 1041–1070.

    Article  CAS  Google Scholar 

  21. Ozeki Y, Tomoda T, Kleiderlein J, Kamiya A, Bord L, Fuji K et al. Disrupted-in-Schizophrenia-1 (DISC-1): mutant truncation prevents binding to NudE-like (NUDEL) and inhibits neurite outgrowth. Proc Natl Acad Sci USA 2003; 100: 289–294.

    Article  CAS  Google Scholar 

  22. Miyoshi K, Honda A, Baba K, Taniguchi M, Oono K, Fujita T et al. Disrupted-In-Schizophrenia 1, a candidate gene for schizophrenia, participates in neurite outgrowth. Mol Psychiatry 2003; 8: 685–694.

    Article  CAS  Google Scholar 

  23. Austin CP, Ma L, Ky B, Morris JA, Shughrue PJ . DISC1 (disrupted in Schizophrenia-1) is expressed in limbic regions of the primate brain. NeuroReport 2003; 14: 951–954.

    Article  CAS  Google Scholar 

  24. Nardi C, Lipska BK, Kozlovsky N, Weinberger DR, Belmaker RH, Agam G . Glycogen synthase kinase (GSK)-3b levels and activity in a neurodevelopmental rat model of schizophrenia. Dev Brain Res 2003; 141: 33–37.

    Article  Google Scholar 

  25. Schneider M, Koch M . Chronic pubertal, but not adult chronic cannabinoid treatment impairs sensorimotor gating, recognition memory, and the performance in a progressive ratio task in adult rats. Neuropsychopharmcology 2003; 28: 1760–1769.

    Article  CAS  Google Scholar 

  26. Cunningham MG, Bhattacharyya S, Benes FM . Amygdalo-cortical sprouting continues into early adulthood: implications for the development of normal and abnormal function during adolescence. J Comp Neurology 2002; 453: 116–130.

    Article  Google Scholar 

  27. Oliver KR, Wainwright A, Edvinsson L, Pickard JD, Hill RG . Immunohistochemical localization of calcitonin receptor-like receptor and receptor activity modifying proteins in human cerebral vasculature. J Cereb Blood Flow Metab 2002; 22: 620–629.

    Article  CAS  Google Scholar 

  28. Morris JA, Kandpal G, Ma L, Austin CP . DISC1 (disrupted-in-schizophrenia 1) is a centrosome-associated protein that interacts with MAP1A, MIPT3, ATF4/5 and NUDEL: regulation and loss of interaction with mutation. Hum Mol Genet 2003; 12: 1591–1608.

    Article  CAS  Google Scholar 

  29. James R, Adams RR, Christie S, Buchanan SR, Porteous DJ, Millar JK . Disrupted in Schizophrenia 1 (DISC1) is a multicompartmentalized protein that predominantly localizes to mitochondria. Mol Cell Neurosci 2004; 26: 112–122.

    Article  CAS  Google Scholar 

  30. O'Donovan MC, Williams NM, Owen MJ . Recent advances in the genetics of schizophrenia. Hum Mol Genetics 2003; 12: R125–R133.

    Article  CAS  Google Scholar 

  31. Sawa A, Snyder SH . Schizophrenia: diverse approaches to a complex disease. Science 2002; 269: 692–695.

    Article  Google Scholar 

  32. Millar JK, Christie S, Porteous DJ . Yeast two-hybrid screens implicate DISC1 in brain development and function. Biochem Biophys Res Commun 2003; 311: 1019–1025.

    Article  CAS  Google Scholar 

  33. Ma L, Liu Y, Ky B, Shughrue PJ, Austin CP, Morris JA . Cloning and characterization of Disc1, the mouse ortholog of DISC1 (disrupted-in-schizophrenia 1). Genomics 2002; 80: 662–672.

    Article  CAS  Google Scholar 

  34. Honda A, Miyoshi K, Baba K, Taniguchi M, Koyama Y, Kuroda S et al. Expression of fasciculation and elongation protein zeta-1 (FEZ1) in the developing rat brain. Mol Brain Res 2004; 122: 89–92.

    Article  CAS  Google Scholar 

  35. Innocenti GM, Ansermet F, Parnas J . Schizophrenia, neurodevelopment and corpus callosum. Mol Psychiatry 2003; 8: 261–274.

    Article  CAS  Google Scholar 

  36. Lieberman JA, Perkins D, Belger A, Chakos M, Jarskov F, Boteva K et al. The early stage of schizophrenia:speculations on patogenesis, pathophysiology, and therapeutic approaches. Biol Psychiatry 2001; 50: 884–897.

    Article  CAS  Google Scholar 

  37. Berretta S, Munno DW, Benes FM . Amygdalar activation alters the hippocampal GABA system: ‘partial’ modeling for postmortem changes in schizophrenia. J Comper Neurobiol 2001; 431: 129–138.

    Article  CAS  Google Scholar 

  38. Smith GN, Lang DJ, Kopala LC, Lapointe JS, Falkai P, Honer WG . Developmental abnormalities of the hippocampus in first-episode schizophrenia. Biol Psychiatry 2003; 53: 555–561.

    Article  Google Scholar 

  39. Benes FM, Vincent SL, Todtenkopf M . The density of pyramidal and nonpyramidal neurons in anterior cingulated cortex of schizophrenic and bipolar subjects. Biol Psychiatry 2001; 50: 395–406.

    Article  CAS  Google Scholar 

  40. Benes FM, McSparren J, Bird ED, Vincent SL . Deficits in small interneurons in prefrontal and cingulated cortices of schizophrenic and schizoaffective patients. Arch Gen Psychiatry 1991; 48: 996–1001.

    Article  CAS  Google Scholar 

  41. Reynolds GP, Zhang ZJ, Beasley CL . Neurochemical correlates of cortical GABAergic deficits in schizophrenia: selective losses of calcium binding protein immunoreactivity. Brain Res Bull 2001; 55: 579–584.

    Article  CAS  Google Scholar 

  42. Reynolds GP, Beasley CL . GABAergic neuronal subtypes in the human frontal cortex-development and deficits in schizophrenia. J Chem Neuroanat 2001; 22: 95–100.

    Article  CAS  Google Scholar 

  43. Tsai G, Coyle JT . Glutamatergic mechanisms in schizophrenia. Annu Rev Pharmacol Toxicol 2002; 42: 165–179.

    Article  CAS  Google Scholar 

  44. Sawa A, Snyder SH . Schizophrenia: neural mechanisms for novel therapies. Mol Medicine 2003; 3–9.

    Article  Google Scholar 

  45. Lewis DA, Volk DW, Hashimoto T . Selective alterations in prefrontal cortical GABA neurotransmission in schizophrenia: a novel target for the treatment of working memory dysfunction. Psychopharmacology 2004; 174: 143–150.

    Article  CAS  Google Scholar 

  46. Wassef A, Baker J, Kochan LD . GABA and schizophrenia: a review of basic science and clinical studies. J Clin Psychopharmacol 2003; 23: 601–640.

    Article  CAS  Google Scholar 

  47. Eyles DW, McGrath JJ, Reynolds GP . Neuronal calcium-binding proteins and schizophrenia. Schizophr Res 2002; 57: 27–34.

    Article  CAS  Google Scholar 

  48. Todtenkopf MS, Benes FM . Distribution of glutamate decarboxylase65-immunoreactive puncta on pyramidal and nonpyramidal neurons in hippocampus of schizophrenic brain. Synapse 1998; 29: 323–332.

    Article  CAS  Google Scholar 

  49. Benes FM, Todtenkopf MS, Vincent SL . Meta-analysis of nonpyramidal neuron (NP) loss in layer II in anterior cingulated cortex (ACCx-II) from three studies of postmortem schizophrenic (SZ) brain. Soc Neurosci Abst 1998; 24: 1275.

    Google Scholar 

  50. Dean B, Hussain T, Hayes W, Scarr E, Kitsoulis S, Hill C et al. Changes in serotonin2A and GABA(A) receptors in schizophrenia: studies on the human dorsolateral prefrontal cortex. J Neurochem 1999; 72: 1593–1599.

    Article  CAS  Google Scholar 

  51. Benes FM, Khan Y, Vincent SL, Wickramasinghe R . Differences in the subregional and cellular distribution of GABA-A receptor binding in the hippocampal formation of schizophrenic brain. Synapse 1996; 22: 338–349.

    Article  CAS  Google Scholar 

  52. Krystal JH, Karper LP, Seibyl JP, Freeman GK, Delaney R, Bremner JD et al. Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans. Psychotomimetic, perceptual, cognitive, and neuroendocrine responses. Arch Gen Psychiatry 1994; 51: 199–214.

    Article  CAS  Google Scholar 

  53. Kaufman MH . The Atlas of Mouse Development. Academic Press: Cambridge, 2001.

    Google Scholar 

  54. Bunney BG, Potkin SG, Bunney WE . Neuropathological studies of brain tissue in schizophrenia. J Psychiatr Res 1997; 31: 159–173.

    Article  CAS  Google Scholar 

  55. Heinz A, Romero B, Gallinat J, Juckel G, Weinberger DR . Molecular brain imaging and the neurobiology and genetics of schizophrenia. Pharmacopsychiatry 2003; 36: 152–157.

    Article  Google Scholar 

  56. Andreasen NC . Pieces of the schizophrenia puzzle fall into place. Neuron 1996; 16: 697–700.

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to I L Schurov.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Schurov, I., Handford, E., Brandon, N. et al. Expression of disrupted in schizophrenia 1 (DISC1) protein in the adult and developing mouse brain indicates its role in neurodevelopment. Mol Psychiatry 9, 1100–1110 (2004). https://doi.org/10.1038/sj.mp.4001574

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.mp.4001574

Keywords

Search

Quick links