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The DISC locus in psychiatric illness

Molecular Psychiatry volume 13, pages 36–64 (2008)Cite this article

Abstract

The DISC locus is located at the breakpoint of a balanced t(1;11) chromosomal translocation in a large and unique Scottish family. This translocation segregates in a highly statistically significant manner with a broad diagnosis of psychiatric illness, including schizophrenia, bipolar disorder and major depression, as well as with a narrow diagnosis of schizophrenia alone. Two novel genes were identified at this locus and due to the high prevalence of schizophrenia in this family, they were named Disrupted-in-Schizophrenia-1 (DISC1) and Disrupted-in-Schizophrenia-2 (DISC2). DISC1 encodes a novel multifunctional scaffold protein, whereas DISC2 is a putative noncoding RNA gene antisense to DISC1. A number of independent genetic linkage and association studies in diverse populations support the original linkage findings in the Scottish family and genetic evidence now implicates the DISC locus in susceptibility to schizophrenia, schizoaffective disorder, bipolar disorder and major depression as well as various cognitive traits. Despite this, with the exception of the t(1;11) translocation, robust evidence for a functional variant(s) is still lacking and genetic heterogeneity is likely. Of the two genes identified at this locus, DISC1 has been prioritized as the most probable candidate susceptibility gene for psychiatric illness, as its protein sequence is directly disrupted by the translocation. Much research has been undertaken in recent years to elucidate the biological functions of the DISC1 protein and to further our understanding of how it contributes to the pathogenesis of schizophrenia. These data are the main subject of this review; however, the potential involvement of DISC2 in the pathogenesis of psychiatric illness is also discussed. A detailed picture of DISC1 function is now emerging, which encompasses roles in neurodevelopment, cytoskeletal function and cAMP signalling, and several DISC1 interactors have also been defined as independent genetic susceptibility factors for psychiatric illness. DISC1 is a hub protein in a multidimensional risk pathway for major mental illness, and studies of this pathway are opening up opportunities for a better understanding of causality and possible mechanisms of intervention.

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References

  1. St Clair D, Blackwood D, Muir W, Carothers A, Walker M, Spowart G et al. Association within a family of a balanced autosomal translocation with major mental illness. Lancet 1990; 336: 13–16.

    Article  CAS  PubMed  Google Scholar 

  2. Blackwood DH, Fordyce A, Walker MT, St Clair DM, Porteous DJ, Muir WJ . Schizophrenia and affective disorders—cosegregation with a translocation at chromosome 1q42 that directly disrupts brain-expressed genes: clinical and P300 findings in a family. Am J Hum Genet 2001; 69: 428–433.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Blackwood DH, Muir WJ . Clinical phenotypes associated with DISC1, a candidate gene for schizophrenia. Neurotox Res 2004; 6: 35–41.

    Article  CAS  PubMed  Google Scholar 

  4. Muir WJ, Gosden CM, Brookes AJ, Fantes J, Evans KL, Maguire SM et al. Direct microdissection and microcloning of a translocation breakpoint region, t(1;11)(q42.2;q21), associated with schizophrenia. Cytogenet Cell Genet 1995; 70: 35–40.

    Article  CAS  PubMed  Google Scholar 

  5. Evans KL, Brown J, Shibasaki Y, Devon RS, He L, Arveiler B et al. A contiguous clone map over 3 Mb on the long arm of chromosome 11 across a balanced translocation associated with schizophrenia. Genomics 1995; 28: 420–428.

    Article  CAS  PubMed  Google Scholar 

  6. Devon RS, Evans KL, Maule JC, Christie S, Anderson S, Brown J et al. Novel transcribed sequences neighbouring a translocation breakpoint associated with schizophrenia. Am J Med Genet 1997; 74: 82–90.

    Article  CAS  PubMed  Google Scholar 

  7. Millar JK, Brown J, Maule JC, Shibasaki Y, Christie S, Lawson D et al. A long-range restriction map across 3 Mb of the chromosome 11 breakpoint region of a translocation linked to schizophrenia: localization of the breakpoint and the search for neighbouring genes. Psychiatr Genet 1998; 8: 175–181.

    Article  CAS  PubMed  Google Scholar 

  8. Semple CA, Devon RS, Le Hellard S, Porteous DJ . Identification of genes from a schizophrenia-linked translocation breakpoint region. Genomics 2001; 73: 123–126.

    Article  CAS  PubMed  Google Scholar 

  9. 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  PubMed  Google Scholar 

  10. Millar JK, Christie S, Anderson S, Lawson D, Hsiao-Wei Loh D, Devon RS et al. Genomic structure and localisation within a linkage hotspot of Disrupted In Schizophrenia 1, a gene disrupted by a translocation segregating with schizophrenia. Mol Psychiatry 2001; 6: 173–178.

    Article  CAS  PubMed  Google Scholar 

  11. Ekelund J, Lichtermann D, Hovatta I, Ellonen P, Suvisaari J, Terwilliger JD et al. Genome-wide scan for schizophrenia in the Finnish population: evidence for a locus on chromosome 7q22. Hum Mol Genet 2000; 9: 1049–1057.

    Article  CAS  PubMed  Google Scholar 

  12. Hovatta I, Varilo T, Suvisaari J, Terwilliger JD, Ollikainen V, Arajarvi R et al. A genomewide screen for schizophrenia genes in an isolated Finnish subpopulation, suggesting multiple susceptibility loci. Am J Hum Genet 1999; 65: 1114–1124.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. 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  PubMed  Google Scholar 

  14. Ekelund J, Hennah W, Hiekkalinna T, Parker A, Meyer J, Lonnqvist J et al. Replication of 1q42 linkage in Finnish schizophrenia pedigrees. Mol Psychiatry 2004; 9: 1037–1041.

    Article  CAS  PubMed  Google Scholar 

  15. Hamshere ML, Bennett P, Williams N, Segurado R, Cardno A, Norton N et al. Genomewide linkage scan in schizoaffective disorder: significant evidence for linkage at 1q42 close to DISC1, and suggestive evidence at 22q11 and 19p13. Arch Gen Psychiatry 2005; 62: 1081–1088.

    Article  CAS  PubMed  Google Scholar 

  16. 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  PubMed  Google Scholar 

  17. Macgregor S, Visscher PM, Knott SA, Thomson P, Porteous DJ, Millar JK et al. A genome scan and follow-up study identify a bipolar disorder susceptibility locus on chromosome 1q42. Mol Psychiatry 2004; 9: 1083–1090.

    Article  CAS  PubMed  Google Scholar 

  18. Curtis D, Kalsi G, Brynjolfsson J, McInnis M, O'Neill J, Smyth C et al. Genome scan of pedigrees multiply affected with bipolar disorder provides further support for the presence of a susceptibility locus on chromosome 12q23–q24, and suggests the presence of additional loci on 1p and 1q. Psychiatr Genet 2003; 13: 77–84.

    PubMed  Google Scholar 

  19. Detera-Wadleigh SD, Badner JA, Berrettini WH, Yoshikawa T, Goldin LR, Turner G et al. A high-density genome scan detects evidence for a bipolar-disorder susceptibility locus on 13q32 and other potential loci on 1q32 and 18p11.2. Proc Natl Acad Sci USA 1999; 96: 5604–5609.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Devon RS, Anderson S, Teague PW, Burgess P, Kipari TM, Semple CA et al. Identification of polymorphisms within Disrupted in Schizophrenia 1 and Disrupted in Schizophrenia 2, and an investigation of their association with schizophrenia and bipolar affective disorder. Psychiatr Genet 2001; 11: 71–78.

    Article  CAS  PubMed  Google Scholar 

  21. Hennah W, Varilo T, Kestila M, Paunio T, Arajarvi R, Haukka J et al. Haplotype transmission analysis provides evidence of association for DISC1 to schizophrenia and suggests sex-dependent effects. Hum Mol Genet 2003; 12: 3151–3159.

    Article  CAS  PubMed  Google Scholar 

  22. Hennah W, Tuulio-Henriksson A, Paunio T, Ekelund J, Varilo T, Partonen T et al. A haplotype within the DISC1 gene is associated with visual memory functions in families with a high density of schizophrenia. Mol Psychiatry 2005; 10: 1097–1103.

    Article  CAS  PubMed  Google Scholar 

  23. Hennah W, Thomson P, Peltonen L, Porteous D . Genes and schizophrenia: beyond schizophrenia: the role of DISC1 in major mental illness. Schizophr Bull 2006; 32: 409–416.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Hodgkinson CA, Goldman D, Jaeger J, Persaud S, Kane JM, Lipsky RH et al. Disrupted in schizophrenia 1 (DISC1): association with schizophrenia, schizoaffective disorder, and bipolar disorder. Am J Hum Genet 2004; 75: 862–872.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Callicott JH, Straub RE, Pezawas L, Egan MF, Mattay VS, Hariri AR et al. Variation in DISC1 affects hippocampal structure and function and increases risk for schizophrenia. Proc Natl Acad Sci USA 2005; 102: 8627–8632.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Qu M, Tang F, Yue W, Ruan Y, Lu T, Liu Z et al. Positive association of the Disrupted-in-Schizophrenia-1 gene (DISC1) with schizophrenia in the Chinese Han population. Am J Med Genet B Neuropsychiatr Genet 2007; 144: 266–270.

    Article  CAS  Google Scholar 

  27. Hashimoto R, Numakawa T, Ohnishi T, Kumamaru E, Yagasaki Y, Ishimoto T et al. Impact of the DISC1 Ser704Cys polymorphism on risk for major depression, brain morphology and ERK signaling. Hum Mol Genet 2006; 15: 3024–3033.

    Article  CAS  PubMed  Google Scholar 

  28. Thomson PA, Wray NR, Millar JK, Evans KL, Hellard SL, Condie A et al. Association between the TRAX/DISC locus and both bipolar disorder and schizophrenia in the Scottish population. Mol Psychiatry 2005; 10: 657–668, 616.

    Article  CAS  PubMed  Google Scholar 

  29. Chen QY, Chen Q, Feng GY, Lindpaintner K, Wang LJ, Chen ZX et al. Case-control association study of Disrupted-in-Schizophrenia-1 (DISC1) gene and schizophrenia in the Chinese population. J Psychiatr Res 2007; 41: 428–434.

    Article  PubMed  Google Scholar 

  30. Kilpinen H, Ylisaukko-Oja T, Hennah W, Palo OM, Varilo T, Vanhala R et al. Association of DISC1 with autism and Asperger syndrome. Mol Psychiatry 2007 Jun 19. [doi:10.1038/sj.mp.4002031].

    Article  PubMed  CAS  Google Scholar 

  31. Kockelkorn TT, Arai M, Matsumoto H, Fukuda N, Yamada K, Minabe Y et al. Association study of polymorphisms in the 5′ upstream region of human DISC1 gene with schizophrenia. Neurosci Lett 2004; 368: 41–45.

    Article  CAS  PubMed  Google Scholar 

  32. Zhang X, Tochigi M, Ohashi J, Maeda K, Kato T, Okazaki Y et al. Association study of the DISC1/TRAX locus with schizophrenia in a Japanese population. Schizophr Res 2005; 79: 175–180.

    Article  PubMed  Google Scholar 

  33. Sachs NA, Sawa A, Holmes SE, Ross CA, DeLisi LE, Margolis RL . A frameshift mutation in Disrupted in Schizophrenia 1 in an American family with schizophrenia and schizoaffective disorder. Mol Psychiatry 2005; 10: 758–764.

    Article  CAS  PubMed  Google Scholar 

  34. Green EK, Norton N, Peirce T, Grozeva D, Kirov G, Owen MJ et al. Evidence that a DISC1 frame-shift deletion associated with psychosis in a single family may not be a pathogenic mutation. Mol Psychiatry 2006; 11: 798–799.

    Article  CAS  PubMed  Google Scholar 

  35. Burdick KE, Hodgkinson CA, Szeszko PR, Lencz T, Ekholm JM, Kane JM et al. DISC1 and neurocognitive function in schizophrenia. Neuroreport 2005; 16: 1399–1402.

    Article  PubMed  Google Scholar 

  36. Cannon TD, Hennah W, van Erp TG, Thompson PM, Lonnqvist J, Huttunen M et al. Association of DISC1/TRAX haplotypes with schizophrenia, reduced prefrontal gray matter, and impaired short- and long-term memory. Arch Gen Psychiatry 2005; 62: 1205–1213.

    Article  CAS  PubMed  Google Scholar 

  37. Gasperoni TL, Ekelund J, Huttunen M, Palmer CG, Tuulio-Henriksson A, Lonnqvist J et al. Genetic linkage and association between chromosome 1q and working memory function in schizophrenia. Am J Med Genet B Neuropsychiatr Genet 2003; 116: 8–16.

    Article  Google Scholar 

  38. Thomson PA, Harris SE, Starr JM, Whalley LJ, Porteous DJ, Deary IJ . Association between genotype at an exonic SNP in DISC1 and normal cognitive aging. Neurosci Lett 2005; 389: 41–45.

    Article  CAS  PubMed  Google Scholar 

  39. Liu YL, Fann CS, Liu CM, Chen WJ, Wu JY, Hung SI et al. A single nucleotide polymorphism fine mapping study of chromosome 1q42.1 reveals the vulnerability genes for schizophrenia, GNPAT and DISC1: association with impairment of sustained attention. Biol Psychiatry 2006; 60: 554–562.

    Article  CAS  PubMed  Google Scholar 

  40. Paunio T, Tuulio-Henriksson A, Hiekkalinna T, Perola M, Varilo T, Partonen T et al. Search for cognitive trait components of schizophrenia reveals a locus for verbal learning and memory on 4q and for visual working memory on 2q. Hum Mol Genet 2004; 13: 1693–1702.

    Article  CAS  PubMed  Google Scholar 

  41. Kimchi-Sarfaty C, Oh JM, Kim IW, Sauna ZE, Calcagno AM, Ambudkar SV et al. A ‘silent’ polymorphism in the MDR1 gene changes substrate specificity. Science 2007; 315: 525–528.

    Article  CAS  PubMed  Google Scholar 

  42. Arguello PA, Gogos JA . Modeling madness in mice: one piece at a time. Neuron 2006; 52: 179–196.

    Article  CAS  PubMed  Google Scholar 

  43. Millar JK, Pickard BS, Mackie S, James R, Christie S, Buchanan SR et al. DISC1 and PDE4B are interacting genetic factors in schizophrenia that regulate cAMP signaling. Science 2005; 310: 1187–1191.

    Article  CAS  PubMed  Google Scholar 

  44. Ishizuka K, Paek M, Kamiya A, Sawa A . A review of Disrupted-In-Schizophrenia-1 (DISC1): neurodevelopment, cognition, and mental conditions. Biol Psychiatry 2006; 59: 1189–1197.

    Article  CAS  PubMed  Google Scholar 

  45. Koike H, Arguello PA, Kvajo M, Karayiorgou M, Gogos JA . Disc1 is mutated in the 129S6/SvEv strain and modulates working memory in mice. Proc Natl Acad Sci USA 2006; 103: 3693–3697.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Clapcote SJ, Roder JC . Deletion polymorphism of Disc1 is common to all 129 mouse substrains: implications for gene-targeting studies of brain function. Genetics 2006; 173: 2407–2410.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Koide T, Moriwaki K, Ikeda K, Niki H, Shiroishi T . Multi-phenotype behavioral characterization of inbred strains derived from wild stocks of Mus musculus. Mamm Genome 2000; 11: 664–670.

    Article  CAS  PubMed  Google Scholar 

  48. Ishizuka K, Chen J, Taya S, Li W, Millar JK, Xu Y et al. Evidence that many of the DISCI isoforms in C57BL/6J mice are also expressed in 129S6/SvEv mice. Mol Psychiatry, (in press).

  49. Sakuraba Y, Sezutsu H, Takahasi KR, Tsuchihashi K, Ichikawa R, Fujimoto N et al. Molecular characterization of ENU mouse mutagenesis and archives. Biochem Biophys Res Commun 2005; 336: 609–616.

    Article  CAS  PubMed  Google Scholar 

  50. Clapcote SJ, Lipina TV, Millar JK, Mackie S, Christie S, Ogawa F et al. Behavioral phenotypes of Disc1 missense mutations in mice. Neuron 2007; 54: 387–402.

    Article  CAS  PubMed  Google Scholar 

  51. Ross CA, Margolis RL, Reading SA, Pletnikov M, Coyle JT . Neurobiology of schizophrenia. Neuron 2006; 52: 139–153.

    Article  CAS  PubMed  Google Scholar 

  52. Hikida T, Jaaro-peled H, Seshadri S, Oishi K, Hookway C, Kong S et al. Dominant-negative DISC1 transgenic mice display schizophrenia-associated phenotypes detected by measures translatable to humans. Proc Natl Acad Sci USA 2007; 104: 14501–14506 Aug; e-pub 0027-8424.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Pletnikov MV, Ayhan Y, Nikolskaia O, Xu Y, Ovanesov M, Huang H et al. Inducible expression of mutant human DISC1 in mice is associated with brain and behavioural abnormalities reminiscent of schizophrenia. Mol Psychiatry 2007 [doi:10.1038/sj.mp.4002079].

    Article  PubMed  CAS  Google Scholar 

  54. Bord L, Wheeler J, Paek M, Saleh M, Lyons-Warren A, Ross CA et al. Primate disrupted-in-schizophrenia-1 (DISC1): high divergence of a gene for major mental illnesses in recent evolutionary history. Neurosci Res 2006; 56: 286–293.

    Article  CAS  PubMed  Google Scholar 

  55. 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  PubMed  Google Scholar 

  56. Ozeki Y, Tomoda T, Kleiderlein J, Kamiya A, Bord L, Fujii 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  PubMed  Google Scholar 

  57. Taylor MS, Devon RS, Millar JK, Porteous DJ . Evolutionary constraints on the Disrupted in Schizophrenia locus. Genomics 2003; 81: 67–77.

    Article  CAS  PubMed  Google Scholar 

  58. Tatusova TA, Madden TL . BLAST 2 Sequences, a new tool for comparing protein and nucleotide sequences. FEMS Microbiol Lett 1999; 174: 247–250.

    Article  CAS  PubMed  Google Scholar 

  59. Kent WJ . BLAT—the BLAST-like alignment tool. Genome Res 2002; 12: 656–664.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Lipska BK, Peters T, Hyde TM, Halim N, Horowitz C, Mitkus S et al. Expression of DISC1 binding partners is reduced in schizophrenia and associated with DISC1 SNPs. Hum Mol Genet 2006; 15: 1245–1258.

    Article  CAS  PubMed  Google Scholar 

  61. Millar JK, Christie S, Semple CA, Porteous DJ . Chromosomal location and genomic structure of the human translin-associated factor X gene (TRAX; TSNAX) revealed by intergenic splicing to DISC1, a gene disrupted by a translocation segregating with schizophrenia. Genomics 2000; 67: 69–77.

    Article  CAS  PubMed  Google Scholar 

  62. Aoki K, Ishida R, Kasai M . Isolation and characterization of a cDNA encoding a Translin-like protein, TRAX. FEBS Lett 1997; 401: 109–112.

    Article  CAS  PubMed  Google Scholar 

  63. Chennathukuzhi VM, Kurihara Y, Bray JD, Hecht NB . Trax (translin-associated factor X), a primarily cytoplasmic protein, inhibits the binding of TB-RBP (translin) to RNA. J Biol Chem 2001; 276: 13256–13263.

    Article  CAS  PubMed  Google Scholar 

  64. Muramatsu T, Ohmae A, Anzai K . BC1 RNA protein particles in mouse brain contain two y-,h-element-binding proteins, translin and a 37 kDa protein. Biochem Biophys Res Commun 1998; 247: 7–11.

    Article  CAS  PubMed  Google Scholar 

  65. 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  PubMed  Google Scholar 

  66. Kamiya A, Kubo K, Tomoda T, Takaki M, Youn R, Ozeki Y et al. A schizophrenia-associated mutation of DISC1 perturbs cerebral cortex development. Nat Cell Biol 2005; 7: 1167–1178.

    Article  PubMed  CAS  Google Scholar 

  67. 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  PubMed  Google Scholar 

  68. Murdoch H, Mackie S, Collins DM, Hill EV, Bolger GB, Klussmann E et al. Isoform-selective susceptibility of DISC1/phosphodiesterase-4 complexes to dissociation by elevated intracellular cAMP levels. J. Neurosci 2007; 27: 9513–9524.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Ogawa F, Kasai M, Akiyama T . A functional link between Disrupted-In-Schizophrenia 1 and the eukaryotic translation initiation factor 3. Biochem Biophys Res Commun 2005; 338: 771–776.

    Article  CAS  PubMed  Google Scholar 

  70. Sawamura N, Sawamura-Yamamoto T, Ozeki Y, Ross CA, Sawa A . A form of DISC1 enriched in nucleus: altered subcellular distribution in orbitofrontal cortex in psychosis and substance/alcohol abuse. Proc Natl Acad Sci USA 2005; 102: 1187–1192.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Millar JK, James R, Christie S, Porteous DJ . Disrupted in schizophrenia 1 (DISC1): subcellular targeting and induction of ring mitochondria. Mol Cell Neurosci 2005; 30: 477–484.

    Article  CAS  PubMed  Google Scholar 

  72. Pei J, Grishin NV . PROMALS: towards accurate multiple sequence alignments of distantly related proteins. Bioinformatics 2007; 23: 802–808.

    Article  CAS  PubMed  Google Scholar 

  73. McGuffin LJ, Bryson K, Jones DT . The PSIPRED protein structure prediction server. Bioinformatics 2000; 16: 404–405.

    Article  CAS  PubMed  Google Scholar 

  74. Thompson JD, Gibson TJ, Plewniak F, Jeanmougin F, Higgins DG . The CLUSTAL_X windows interface: flexible strategies for multiple sequence alignment aided by quality analysis tools. Nucleic Acids Res 1997; 25: 4876–4882.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Kamiya A, Tomoda T, Chang J, Takaki M, Zhan C, Morita M et al. DISC1-NDEL1/NUDEL protein interaction, an essential component for neurite outgrowth, is modulated by genetic variations of DISC1. Hum Mol Genet 2006; 15: 3313–3323.

    Article  CAS  PubMed  Google Scholar 

  76. 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  PubMed  Google Scholar 

  77. Schurov L, Handford EJ, Brandon NJ, Whiting PJ . Expression of disrupted in schizophrenia 1 (DISC1) protein in the adult and developing mouse brain indicates its role in neurodevelopment. Mol Psychiatry 2004; 9: 1100–1110.

    Article  CAS  PubMed  Google Scholar 

  78. 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  PubMed  Google Scholar 

  79. Harrison PJ . The hippocampus in schizophrenia: a review of the neuropathological evidence and its pathophysiological implications. Psychopharmacology (Berl) 2004; 174: 151–162.

    Article  CAS  Google Scholar 

  80. Bachevalier J, Alvarado MC, Malkova L . Memory and socioemotional behavior in monkeys after hippocampal damage incurred in infancy or in adulthood. Biol Psychiatry 1999; 46: 329–339.

    Article  CAS  PubMed  Google Scholar 

  81. Lipska BK . Using animal models to test a neurodevelopmental hypothesis of schizophrenia. J Psychiatry Neurosci 2004; 29: 282–286.

    PubMed  PubMed Central  Google Scholar 

  82. Marquis JP, Goulet S, Dore FY . Neonatal lesions of the ventral hippocampus in rats lead to prefrontal cognitive deficits at two maturational stages. Neuroscience 2006; 140: 759–767.

    Article  CAS  PubMed  Google Scholar 

  83. Austin CP, Ky B, Ma L, Morris JA, Shughrue PJ . Expression of Disrupted-In-Schizophrenia-1, a schizophrenia-associated gene, is prominent in the mouse hippocampus throughout brain development. Neuroscience 2004; 124: 3–10.

    Article  CAS  PubMed  Google Scholar 

  84. Brandon NJ, Handford EJ, Schurov I, Rain JC, Pelling M, Duran-Jimeniz B et al. Disrupted in Schizophrenia 1 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  PubMed  Google Scholar 

  85. Brandon NJ, Schurov I, Camargo LM, Handford EJ, Duran-Jimeniz B, Hunt P et al. Subcellular targeting of DISC1 is dependent on a domain independent from the Nudel binding site. Mol Cell Neurosci 2005; 28: 613–624.

    Article  CAS  PubMed  Google Scholar 

  86. Miyoshi K, Asanuma M, Miyazaki I, Diaz-Corrales FJ, Katayama T, Tohyama M et al. DISC1 localizes to the centrosome by binding to kendrin. Biochem Biophys Res Comm 2005; 317: 1195–1199.

    Article  CAS  Google Scholar 

  87. Shinoda T, Taya S, Tsuboi D, Hikita T, Matsuzawa R, Kuroda S et al. DISC1 regulates neurotrophin-induced axon elongation via interaction with Grb2. J Neurosci 2007; 27: 4–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Taya S, Shinoda T, Tsuboi D, Asaki J, Nagai K, Hikita T et al. DISC1 regulates the transport of the NUDEL/LIS1/14-3-3epsilon complex through kinesin-1. J Neurosci 2007; 27: 15–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Hattori T, Baba K, Matsuzaki S, Honda A, Miyoshi K, Inoue K et al. A novel DISC1-interacting partner DISC1-Binding Zinc-finger protein: implication in the modulation of DISC1-dependent neurite outgrowth. Mol Psychiatry 2007; 12: 398–407.

    Article  CAS  PubMed  Google Scholar 

  90. Pletnikov MV, Xu Y, Ovanesov MV, Kamiya A, Sawa A, Ross CA . PC12 cell model of inducible expression of mutant DISC1: New evidence for a dominant-negative mechanism of abnormal neuronal differentiation. Neurosci Res 2007; 58: 234–244.

    Article  CAS  PubMed  Google Scholar 

  91. Kirkpatrick B, Xu L, Cascella N, Ozeki Y, Sawa A, Roberts RC . DISC1 immunoreactivity at the light and ultrastructural level in the human neocortex. J Comp Neurol 2006; 497: 436–450.

    Article  PubMed  Google Scholar 

  92. Torrey EF, Webster M, Knable M, Johnston N, Yolken RH . The stanley foundation brain collection and neuropathology consortium. Schizophr Res 2000; 44: 151–155.

    Article  CAS  PubMed  Google Scholar 

  93. Maeda K, Nwulia E, Chang J, Balkissoon R, Ishizuka K, Chen H et al. Differential expression of disrupted-in-schizophrenia (DISC1) in bipolar disorder. Biol Psychiatry 2006; 60: 929–935.

    Article  PubMed  Google Scholar 

  94. Chiba S, Hashimoto R, Hattori S, Yohda M, Lipska B, Weinberger DR et al. Effect of antipsychotic drugs on DISC1 and dysbindin expression in mouse frontal cortex and hippocampus. J Neural Transm 2006; 113: 1337–1346.

    Article  CAS  PubMed  Google Scholar 

  95. Camargo LM, Collura V, Rain J-C, Mizuguchi K, Hermjakob H, Kerrien S et al. Disrupted in Schizophrenia 1 Interactome: evidence for the close connectivity of risk genes and a potential synaptic basis for schizophrenia. Molecular Psychiatry 2007; 12: 74–86.

    Article  CAS  PubMed  Google Scholar 

  96. 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  PubMed  Google Scholar 

  97. Houslay MD, Adams DR . PDE4 cAMP phosphodiesterases: modular enzymes that orchestrate signalling cross-talk, desensitization and compartmentalization. Biochem J 2003; 370 (Part 1): 1–18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Davis RL . Physiology and biochemistry of Drosophila learning mutants. Physiol Rev 1996; 76: 299–317.

    Article  CAS  PubMed  Google Scholar 

  99. Kim YT, Wu CF . Reduced growth cone motility in cultured neurons from Drosophila memory mutants with a defective cAMP cascade. J Neurosci 1996; 16: 5593–5602.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Delgado R, Davis R, Bono MR, Latorre R, Labarca P . Outward currents in Drosophila larval neurons: dunce lacks a maintained outward current component downregulated by cAMP. J Neurosci 1998; 18: 1399–1407.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Zhao ML, Wu CF . Alterations in frequency coding and activity dependence of excitability in cultured neurons of Drosophila memory mutants. J Neurosci 1997; 17: 2187–2199.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Lee D, O'Dowd DK . cAMP-dependent plasticity at excitatory cholinergic synapses in Drosophila neurons: alterations in the memory mutant dunce. J Neurosci 2000; 20: 2104–2111.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Zhang HT, Huang Y, Suvarna NU, Deng C, Crissman AM, Hopper AT et al. Effects of the novel PDE4 inhibitors MEM1018 and MEM1091 on memory in the radial-arm maze and inhibitory avoidance tests in rats. Psychopharmacology (Berl) 2005; 179: 613–619.

    Article  CAS  Google Scholar 

  104. Zhang HT, Crissman AM, Dorairaj NR, Chandler LJ, O'Donnell JM . Inhibition of cyclic AMP phosphodiesterase (PDE4) reverses memory deficits associated with NMDA receptor antagonism. Neuropsychopharmacology 2000; 23: 198–204.

    Article  CAS  PubMed  Google Scholar 

  105. Giorgi M, Modica A, Pompili A, Pacitti C, Gasbarri A . The induction of cyclic nucleotide phosphodiesterase 4 gene (PDE4D) impairs memory in a water maze task. Behav Brain Res 2004; 154: 99–106.

    Article  CAS  PubMed  Google Scholar 

  106. Rutten K, Prickaerts J, Blokland A . Rolipram reverses scopolamine-induced and time-dependent memory deficits in object recognition by different mechanisms of action. Neurobiol Learn Mem 2006; 85: 132–138.

    Article  CAS  PubMed  Google Scholar 

  107. Rutten K, Prickaerts J, Hendrix M, van der Staay FJ, Sik A, Blokland A . Time-dependent involvement of cAMP and cGMP in consolidation of object memory: studies using selective phosphodiesterase type 2, 4 and 5 inhibitors. Eur J Pharmacol 2007; 558: 107–112.

    Article  CAS  PubMed  Google Scholar 

  108. Rutten K, Lieben C, Smits L, Blokland A . The PDE4 inhibitor rolipram reverses object memory impairment induced by acute tryptophan depletion in the rat. Psychopharmacology (Berl) 2007; 192: 275–282.

    Article  CAS  Google Scholar 

  109. Zhang HT, O'Donnell JM . Effects of rolipram on scopolamine-induced impairment of working and reference memory in the radial-arm maze tests in rats. Psychopharmacology (Berl) 2000; 150: 311–316.

    Article  CAS  Google Scholar 

  110. Huang Z, Dias R, Jones T, Liu S, Styhler A, Claveau D et al. L-454,560, a potent and selective PDE4 inhibitor with in vivo efficacy in animal models of asthma and cognition. Biochem Pharmacol 2007; 73: 1971–1981.

    Article  CAS  PubMed  Google Scholar 

  111. Ahmed T, Frey S, Frey JU . Regulation of the phosphodiesterase PDE4B3-isotype during long-term potentiation in the area dentata in vivo. Neuroscience 2004; 124: 857–867.

    Article  CAS  PubMed  Google Scholar 

  112. Hajjhussein H, Suvarna NU, Gremillion C, Chandler LJ, O'Donnell JM . Changes in NMDA receptor-induced cyclic nucleotide synthesis regulate the age-dependent increase in PDE4A expression in primary cortical cultures. Brain Res 2007; 1149: 58–68.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Walikonis RS, Poduslo JF . Activity of cyclic AMP phosphodiesterases and adenylyl cyclase in peripheral nerve after crush and permanent transection injuries. J Biol Chem 1998; 273: 9070–9077.

    Article  CAS  PubMed  Google Scholar 

  114. Sommer N, Martin R, McFarland HF, Quigley L, Cannella B, Raine CS et al. Therapeutic potential of phosphodiesterase type 4 inhibition in chronic autoimmune demyelinating disease. J Neuroimmunol 1997; 79: 54–61.

    Article  CAS  PubMed  Google Scholar 

  115. Nikulina E, Tidwell JL, Dai HN, Bregman BS, Filbin MT . The phosphodiesterase inhibitor rolipram delivered after a spinal cord lesion promotes axonal regeneration and functional recovery. Proc Natl Acad Sci USA 2004; 101: 8786–8790.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Pickard BS, Thomson PA, Christoforou A, Evans KL, Morris SW, Porteous DJ et al. The PDE4B gene confers sex-specific protection against schizophrenia. Psychiatr Genet 2007; 17: 129–133.

    Article  PubMed  Google Scholar 

  117. Tomppo L, Hennah W, Lahermo P, Loukola A, Ekelund J, Partonen T et al. Association evidence from NUDEL and PDE4D support the DISC1-pathway concept in the etiology of schizophrenia. American journal of medical genetics 2006; 141B: 717.

    Google Scholar 

  118. Zhang HT, Huang Y, Jin SL, Frith SA, Suvarna N, Conti M et al. Antidepressant-like profile and reduced sensitivity to rolipram in mice deficient in the PDE4D phosphodiesterase enzyme. Neuropsychopharmacology 2002; 27: 587–595.

    CAS  PubMed  Google Scholar 

  119. O'Donnell JM, Zhang HT . Antidepressant effects of inhibitors of cAMP phosphodiesterase (PDE4). Trends Pharmacol Sci 2004; 25: 158–163.

    Article  CAS  PubMed  Google Scholar 

  120. Gould TD, Manji HK . Signaling networks in the pathophysiology and treatment of mood disorders. J Psychosom Res 2002; 53: 687–697.

    Article  PubMed  Google Scholar 

  121. Tardito D, Perez J, Tiraboschi E, Musazzi L, Racagni G, Popoli M . Signaling pathways regulating gene expression, neuroplasticity, and neurotrophic mechanisms in the action of antidepressants: a critical overview. Pharmacol Rev 2006; 58: 115–134.

    Article  CAS  PubMed  Google Scholar 

  122. Duman RS . Pathophysiology of depression: the concept of synaptic plasticity. Eur Psychiatry 2002; 17 (Suppl 3): 306–310.

    Article  PubMed  Google Scholar 

  123. Duman RS . Synaptic plasticity and mood disorders. Mol Psychiatry 2002; 7 (Suppl 1): S29–S34.

    Article  CAS  PubMed  Google Scholar 

  124. Kanes SJ, Tokarczyk J, Siegel SJ, Bilker W, Abel T, Kelly MP . Rolipram: a specific phosphodiesterase 4 inhibitor with potential antipsychotic activity. Neuroscience 2007; 144: 239–246.

    Article  CAS  PubMed  Google Scholar 

  125. Siuciak JA, Chapin DS, McCarthy SA, Martin AN . Antipsychotic profile of rolipram: efficacy in rats and reduced sensitivity in mice deficient in the phosphodiesterase-4B (PDE4B) enzyme. Psychopharmacology (Berl) 2007; 192: 415–424.

    Article  CAS  Google Scholar 

  126. McPhee I, Pooley L, Lobban M, Bolger G, Houslay MD . Identification, characterization and regional distribution in brain of RPDE-6 (RNPDE4A5), a novel splice variant of the PDE4A cyclic AMP phosphodiesterase family. Biochem J 1995; 310 (Part 3): 965–974.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Cherry JA, Davis RL . Cyclic AMP phosphodiesterases are localized in regions of the mouse brain associated with reinforcement, movement, and affect. J Comp Neurol 1999; 407: 287–301.

    Article  CAS  PubMed  Google Scholar 

  128. Iona S, Cuomo M, Bushnik T, Naro F, Sette C, Hess M et al. Characterization of the rolipram-sensitive, cyclic AMP-specific phosphodiesterases: identification and differential expression of immunologically distinct forms in the rat brain. Mol Pharmacol 1998; 53: 23–32.

    Article  CAS  PubMed  Google Scholar 

  129. D'Sa C, Tolbert LM, Conti M, Duman RS . Regulation of cAMP-specific phosphodiesterases type 4B and 4D (PDE4) splice variants by cAMP signaling in primary cortical neurons. J Neurochem 2002; 81: 745–757.

    Article  CAS  PubMed  Google Scholar 

  130. Miro X, Perez-Torres S, Puigdomenech P, Palacios JM, Mengod G . Differential distribution of PDE4D splice variant mRNAs in rat brain suggests association with specific pathways and presynaptical localization. Synapse 2002; 45: 259–269.

    Article  CAS  PubMed  Google Scholar 

  131. Takahashi M, Terwilliger R, Lane C, Mezes PS, Conti M, Duman RS . Chronic antidepressant administration increases the expression of cAMP-specific phosphodiesterase 4A and 4B isoforms. J Neurosci 1999; 19: 610–618.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Cho CH, Cho DH, Seo MR, Juhnn YS . Differential changes in the expression of cyclic nucleotide phosphodiesterase isoforms in rat brains by chronic treatment with electroconvulsive shock. Exp Mol Med 2000; 32: 110–114.

    Article  CAS  PubMed  Google Scholar 

  133. Miro X, Perez-Torres S, Artigas F, Puigdomenech P, Palacios JM, Mengod G . Regulation of cAMP phosphodiesterase mRNAs expression in rat brain by acute and chronic fluoxetine treatment. An in situ hybridization study. Neuropharmacology 2002; 43: 1148–1157.

    Article  CAS  PubMed  Google Scholar 

  134. Dlaboga D, Hajjhussein H, O'Donnell JM . Regulation of phosphodiesterase-4 (PDE4) expression in mouse brain by repeated antidepressant treatment: comparison with rolipram. Brain Res 2006; 1096: 104–112.

    Article  CAS  PubMed  Google Scholar 

  135. Sun X, Young LT, Wang JF, Grof P, Turecki G, Rouleau GA et al. Identification of lithium-regulated genes in cultured lymphoblasts of lithium responsive subjects with bipolar disorder. Neuropsychopharmacology 2004; 29: 799–804.

    Article  CAS  PubMed  Google Scholar 

  136. Polesskaya OO, Smith RF, Fryxell KJ . Chronic nicotine doses down-regulate PDE4 isoforms that are targets of antidepressants in adolescent female rats. Biol Psychiatry 2007; 61: 56–64.

    Article  CAS  PubMed  Google Scholar 

  137. Baillie GS, MacKenzie SJ, McPhee I, Houslay MD . Sub-family selective actions in the ability of Erk2 MAP kinase to phosphorylate and regulate the activity of PDE4 cyclic AMP-specific phosphodiesterases. Br J Pharmacol 2000; 131: 811–819.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Cherry JA, Thompson BE, Pho V . Diazepam and rolipram differentially inhibit cyclic AMP-specific phosphodiesterases PDE4A1 and PDE4B3 in the mouse. Biochim Biophys Acta 2001; 1518: 27–35.

    Article  CAS  PubMed  Google Scholar 

  139. Reiner O, Carrozzo R, Shen Y, Wehnert M, Faustinella F, Dobyns WB et al. Isolation of a Miller-Dieker lissencephaly gene containing G protein beta-subunit-like repeats. Nature 1993; 364: 717–721.

    Article  CAS  PubMed  Google Scholar 

  140. Lo Nigro C, Chong CS, Smith AC, Dobyns WB, Carrozzo R, Ledbetter DH . Point mutations and an intragenic deletion in LIS1, the lissencephaly causative gene in isolated lissencephaly sequence and Miller-Dieker syndrome. Hum Mol Genet 1997; 6: 157–164.

    Article  CAS  PubMed  Google Scholar 

  141. Kato M, Dobyns WB . Lissencephaly and the molecular basis of neuronal migration. Hum Mol Genet 2003; 12 (Spec No 1): R89–R96.

    Article  CAS  PubMed  Google Scholar 

  142. Hirotsune S, Fleck MW, Gambello MJ, Bix GJ, Chen A, Clark GD et al. Graded reduction of Pafah1b1 (Lis1) activity results in neuronal migration defects and early embryonic lethality. Nature Genetics 1998; 19: 333–339.

    Article  CAS  PubMed  Google Scholar 

  143. Gambello MJ, Darling DL, Yingling J, Tanaka T, Gleeson JG, Wynshaw-Boris A . Multiple dose-dependent effects of Lis1 on cerebral cortical development. J Neurosci 2003; 23: 1719–1729.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Wang Y, Baraban SC . Granule cell dispersion and aberrant neurogenesis in the adult hippocampus of an LIS1 mutant mouse. Dev Neurosci 2007; 29: 91–98.

    Article  CAS  PubMed  Google Scholar 

  145. Xiang X, Osmani AH, Osmani SA, Xin M, Morris NR . NudF, a nuclear migration gene in Aspergillus nidulans, is similar to the human LIS-1 gene required for neuronal migration. Mol Biol Cell 1995; 6: 297–310.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Beckwith SM, Roghi CH, Liu B, Ronald Morris N . The ‘8-kD’ cytoplasmic dynein light chain is required for nuclear migration and for dynein heavy chain localization in Aspergillus nidulans. J Cell Biol 1998; 143: 1239–1247.

    Article  PubMed  PubMed Central  Google Scholar 

  147. Xiang X, Beckwith SM, Morris NR . Cytoplasmic dynein is involved in nuclear migration in Aspergillus nidulans. Proc Natl Acad Sci USA 1994; 91: 2100–2104.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Xiang X, Zuo W, Efimov VP, Morris NR . Isolation of a new set of Aspergillus nidulans mutants defective in nuclear migration. Current Genetics 1999; 35: 626–630.

    Article  CAS  PubMed  Google Scholar 

  149. 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  PubMed  PubMed Central  Google Scholar 

  150. 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  PubMed  Google Scholar 

  151. 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  PubMed  Google Scholar 

  152. 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  PubMed  Google Scholar 

  153. Feng Y, Walsh CA . Mitotic spindle regulation by Nde1 controls cerebral cortical size. Neuron 2004; 44: 279–293.

    Article  CAS  PubMed  Google Scholar 

  154. Sasaki S, Mori D, Toyo-oka K, Chen A, Garrett-Beal L, Muramatsu M et al. Complete loss of Ndel1 results in neuronal migration defects and early embryonic lethality. Mol Cell Biol 2005; 25: 7812–7827.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Badano JL, Teslovich TM, Katsanis N . The centrosome in human genetic disease. Nat Rev Genet 2005; 6: 194–205.

    Article  CAS  PubMed  Google Scholar 

  156. Lambert de Rouvroit C, Goffinet AM . Neuronal migration. Mech Dev 2001; 105: 47–56.

    Article  CAS  PubMed  Google Scholar 

  157. Tsai LH, Gleeson JG . Nucleokinesis in neuronal migration. Neuron 2005; 46: 383–388.

    Article  CAS  PubMed  Google Scholar 

  158. Shu T, Ayala R, Nguyen MD, Xie Z, Gleeson JG, Tsai LH . Ndel1 operates in a common pathway with LIS1 and cytoplasmic dynein to regulate cortical neuronal positioning. Neuron 2004; 44: 263–277.

    Article  CAS  PubMed  Google Scholar 

  159. Tanaka T, Serneo FF, Higgins C, Gambello MJ, Wynshaw-Boris A, Gleeson JG . Lis1 and doublecortin function with dynein to mediate coupling of the nucleus to the centrosome in neuronal migration. J Cell Biol 2004; 165: 709–721.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Toyo-Oka K, Sasaki S, Yano Y, Mori D, Kobayashi T, Toyoshima YY et al. Recruitment of katanin p60 by phosphorylated NDEL1, an LIS1 interacting protein, is essential for mitotic cell division and neuronal migration. Hum Mol Genet 2005; 14: 3113–3128.

    Article  CAS  PubMed  Google Scholar 

  161. Solecki DJ, Model L, Gaetz J, Kapoor TM, Hatten ME . Par6[alpha] signaling controls glial-guided neuronal migration. Nature Neuroscience 2004; 7: 1195–1203.

    Article  CAS  PubMed  Google Scholar 

  162. Caspi M, Atlas R, Kantor A, Sapir T, Reiner O . Interaction between LIS1 and doublecortin, two lissencephaly gene products. Hum Mol Genet 2000; 9: 2205–2213.

    Article  CAS  PubMed  Google Scholar 

  163. Sapir T, Elbaum M, Reiner O . Reduction of microtubule catastrophe events by LIS1, platelet-activating factor acetylhydrolase subunit. EMBO Journal 1997; 16: 6977–6984.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Liu Z, Steward R, Luo L . Drosophila Lis1 is required for neuroblast proliferation, dendritic elaboration and axonal transport. Nature Cell Biology 2000; 2: 776–783.

    Article  CAS  PubMed  Google Scholar 

  165. Faulkner NE, Dujardin DL, Tai CY, Vaughan KT, O'Connell CB, Wang Y et al. A role for the lissencephaly gene LIS1 in mitosis and cytoplasmic dynein function. Nat Cell Biol 2000; 2: 784–791.

    Article  CAS  PubMed  Google Scholar 

  166. Siller KH, Serr M, Steward R, Hays TS, Doe CQ . Live imaging of Drosophila brain neuroblasts reveals a role for Lis1/dynactin in spindle assembly and mitotic checkpoint control. Mol Biol Cell 2005; 16: 5127–5140.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Yan X, Li F, Liang Y, Shen Y, Zhao X, Huang Q et al. Human Nudel and NudE as regulators of cytoplasmic dynein in poleward protein transport along the mitotic spindle. Mol Cell Biol 2003; 23: 1239–1250.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Reiner O, Albrecht U, Gordon M, Chianese K, Wong C, Gal-Gerber O et al. Lissencephaly gene (LIS1) expression in the CNS suggests a role in neuronal migration. J Neurosci 1995; 15: 3730–3738.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  170. Hayashi MAF, Pires RS, Reboucas NA, Britto LRG, Camargo ACM . Expression of endo-oligopeptidase A in the rat central nervous system: a non-radioactive in situ hybridization study. Molecular Brain Research 2001; 89: 86–93.

    Article  CAS  PubMed  Google Scholar 

  171. Smith DS, Niethammer M, Ayala R, Zhou Y, Gambello MJ, Wynshaw-Boris A et al. Regulation of cytoplasmic dynein behaviour and microtubule organization by mammalian Lis1. Nat Cell Biol 2000; 2: 767–775.

    Article  CAS  PubMed  Google Scholar 

  172. Hattori M, Adachi H, Tsujimoto M, Arai H, Inoue K . Miller-Dieker lissencephaly gene encodes a subunit of brain platelet-activating factor. Nature 1994; 370: 216–218.

    Article  CAS  PubMed  Google Scholar 

  173. Hayashi MAF, Portaro FCV, Bastos MF, Guerreiro JR, Oliveira V, Gorrao SS et al. Inhibition of NUDEL (nuclear distribution element-like)-oligopeptidase activity by disrupted-in-schizophrenia 1. Proceedings of the National Academy of Sciences of the United States of America 2005; 102: 3828–3833.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Camargo ACM, Caldo H, Emson PC . Degradation of neurotensin by rabbit brain endo-oligopeptidase A and endo-oligopeptidase B (proline-endopeptidase). Biochemical and Biophysical Research Communications 1983; 116: 1151–1159.

    Article  CAS  PubMed  Google Scholar 

  175. Camargo ACM, Shapanka R, Greene LJ . Preparation, assay, and partial characterization of a neutral endopeptidase from rabbit brain. Biochemistry 1973; 12: 1838–1844.

    Article  CAS  PubMed  Google Scholar 

  176. Tabares-Seisdedos R, Escamez T, Martinez-Gimenez JA, Balanza V, Salazar J, Selva G et al. Variations in genes regulating neuronal migration predict reduced prefrontal cognition in schizophrenia and bipolar subjects from mediterranean Spain: A preliminary study. Neuroscience 2006; 139: 1289–1300.

    Article  CAS  PubMed  Google Scholar 

  177. Hennah W, Tomppo L, Hiekkalinna T, Palo OM, Kilpinen H, Ekelund J et al. Families with the risk allele of DISC1 reveal a link between schizophrenia and another component of the same molecular pathway, NDE1. Hum Mol Genet 2007; 16: 453–462.

    Article  CAS  PubMed  Google Scholar 

  178. Layfield R, Fergusson J, Aitken A, Lowe J, Landon M, Mayer RJ . Neurofibrillary tangles of Alzheimer's disease brains contain 14-3-3 proteins. Neurosci Lett 1996; 209: 57–60.

    Article  CAS  PubMed  Google Scholar 

  179. Agarwal-Mawal A, Qureshi HY, Cafferty PW, Yuan Z, Han D, Lin R et al. 14-3-3 connects glycogen synthase kinase-3 beta to tau within a brain microtubule-associated tau phosphorylation complex. J Biol Chem 2003; 278: 12722–12728.

    Article  CAS  PubMed  Google Scholar 

  180. Hashiguchi M, Sobue K, Paudel HK . 14-3-3zeta is an effector of tau protein phosphorylation. J Biol Chem 2000; 275: 25247–25254.

    Article  CAS  PubMed  Google Scholar 

  181. Ostrerova N, Petrucelli L, Farrer M, Mehta N, Choi P, Hardy J et al. alpha-Synuclein shares physical and functional homology with 14-3-3 proteins. J Neurosci 1999; 19: 5782–5791.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Banfi S, Servadio A, Chung MY, Kwiatkowski Jr TJ, McCall AE, Duvick LA et al. Identification and characterization of the gene causing type 1 spinocerebellar ataxia. Nat Genet 1994; 7: 513–520.

    Article  CAS  PubMed  Google Scholar 

  183. Chen HK, Fernandez-Funez P, Acevedo SF, Lam YC, Kaytor MD, Fernandez MH et al. Interaction of Akt-phosphorylated ataxin-1 with 14-3-3 mediates neurodegeneration in spinocerebellar ataxia type 1. Cell 2003; 113: 457–468.

    Article  CAS  PubMed  Google Scholar 

  184. Dougherty MK, Morrison DK . Unlocking the code of 14-3-3. J Cell Sci 2004; 117 (Part 10): 1875–1884.

    Article  CAS  PubMed  Google Scholar 

  185. Toyo-oka K, Shionoya A, Gambello MJ, Cardoso C, Leventer R, Ward HL et al. 14-3-3epsilon is important for neuronal migration by binding to NUDEL: a molecular explanation for Miller-Dieker syndrome. Nat Genet 2003; 34: 274–285.

    Article  CAS  PubMed  Google Scholar 

  186. Toyooka K, Muratake T, Tanaka T, Igarashi S, Watanabe H, Takeuchi H et al. 14-3-3 protein eta chain gene (YWHAH) polymorphism and its genetic association with schizophrenia. Am J Med Genet 1999; 88: 164–167.

    Article  CAS  PubMed  Google Scholar 

  187. Bell R, Munro J, Russ C, Powell JF, Bruinvels A, Kerwin RW et al. Systematic screening of the 14-3-3 eta (eta) chain gene for polymorphic variants and case-control analysis in schizophrenia. Am J Med Genet 2000; 96: 736–743.

    Article  CAS  PubMed  Google Scholar 

  188. Wong AH, Macciardi F, Klempan T, Kawczynski W, Barr CL, Lakatoo S et al. Identification of candidate genes for psychosis in rat models, and possible association between schizophrenia and the 14-3-3eta gene. Mol Psychiatry 2003; 8: 156–166.

    Article  CAS  PubMed  Google Scholar 

  189. Jia Y, Yu X, Zhang B, Yuan Y, Xu Q, Shen Y et al. An association study between polymorphisms in three genes of 14-3-3 (tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein) family and paranoid schizophrenia in northern Chinese population. Eur Psychiatry 2004; 19: 377–379.

    Article  PubMed  Google Scholar 

  190. Middleton FA, Peng L, Lewis DA, Levitt P, Mirnics K . Altered expression of 14-3-3 genes in the prefrontal cortex of subjects with schizophrenia. Neuropsychopharmacology 2005; 30: 974–983.

    Article  CAS  PubMed  Google Scholar 

  191. Cecconi D, Mion S, Astner H, Domenici E, Righetti PG, Carboni L . Proteomic analysis of rat cortical neurons after fluoxetine treatment. Brain Res 2007; 1135: 41–51.

    Article  CAS  PubMed  Google Scholar 

  192. Lowenstein EJ, Daly RJ, Batzer AG, Li W, Margolis B, Lammers R et al. The SH2 and SH3 domain-containing protein GRB2 links receptor tyrosine kinases to ras signaling. Cell 1992; 70: 431–442.

    Article  CAS  PubMed  Google Scholar 

  193. Oldenhof J, Vickery R, Anafi M, Oak J, Ray A, Schoots O et al. SH3 binding domains in the dopamine D4 receptor. Biochemistry 1998; 37: 15726–15736.

    Article  CAS  PubMed  Google Scholar 

  194. Oldenhof J, Ray A, Vickery R, Van Tol HH . SH3 ligands in the dopamine D3 receptor. Cell Signal 2001; 13: 411–416.

    Article  CAS  PubMed  Google Scholar 

  195. Liu YF, Deth RC, Devys D . SH3 domain-dependent association of huntingtin with epidermal growth factor receptor signaling complexes. J Biol Chem 1997; 272: 8121–8124.

    Article  CAS  PubMed  Google Scholar 

  196. Beard MB, O'Connell JC, Bolger GB, Houslay MD . The unique N-terminal domain of the cAMP phosphodiesterase PDE4D4 allows for interaction with specific SH3 domains. FEBS Lett 1999; 460: 173–177.

    Article  CAS  PubMed  Google Scholar 

  197. Venezia V, Russo C, Repetto E, Nizzari M, Violani E, Carlo P et al. Apoptotic cell death and amyloid precursor protein signaling in neuroblastoma SH-SY5Y cells. Ann NY Acad Sci 2004; 1030: 339–347.

    Article  CAS  PubMed  Google Scholar 

  198. Russo C, Dolcini V, Salis S, Venezia V, Violani E, Carlo P et al. Signal transduction through tyrosine-phosphorylated carboxy-terminal fragments of APP via an enhanced interaction with Shc/Grb2 adaptor proteins in reactive astrocytes of Alzheimer's disease brain. Ann NY Acad Sci 2002; 973: 323–333.

    Article  CAS  PubMed  Google Scholar 

  199. Russo C, Dolcini V, Salis S, Venezia V, Zambrano N, Russo T et al. Signal transduction through tyrosine-phosphorylated C-terminal fragments of amyloid precursor protein via an enhanced interaction with Shc/Grb2 adaptor proteins in reactive astrocytes of Alzheimer's disease brain. J Biol Chem 2002; 277: 35282–35288.

    Article  CAS  PubMed  Google Scholar 

  200. Zhou D, Noviello C, D'Ambrosio C, Scaloni A, D'Adamio L . Growth factor receptor-bound protein 2 interaction with the tyrosine-phosphorylated tail of amyloid beta precursor protein is mediated by its Src homology 2 domain. J Biol Chem 2004; 279: 25374–25380.

    Article  CAS  PubMed  Google Scholar 

  201. Nizzari M, Venezia V, Repetto E, Caorsi V, Magrassi R, Gagliani MC et al. Amyloid precursor protein and Presenilin1 interact with the adaptor GRB2 and modulate ERK 1,2 signaling. J Biol Chem 2007; 282: 13833–13844.

    Article  CAS  PubMed  Google Scholar 

  202. 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  PubMed  Google Scholar 

  203. Ma L, Huang YZ, Pitcher GM, Valtschanoff JG, Ma YH, Feng LY et al. Ligand-dependent recruitment of the ErbB4 signaling complex into neuronal lipid rafts. J Neurosci 2003; 23: 3164–3175.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  204. Bloom L, Horvitz HR . The Caenorhabditis elegans gene unc-76 and its human homologs define a new gene family involved in axonal outgrowth and fasciculation. Proc Natl Acad Sci USA 1997; 94: 3414–3419.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  205. 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. Brain Res Mol Brain Res 2004; 122: 89–92.

    Article  CAS  PubMed  Google Scholar 

  206. Ikuta J, Maturana A, Fujita T, Okajima T, Tatematsu K, Tanizawa K et al. Fasciculation and elongation protein zeta-1 (FEZ1) participates in the polarization of hippocampal neuron by controlling the mitochondrial motility. Biochem Biophys Res Commun 2007; 353: 127–132.

    Article  CAS  PubMed  Google Scholar 

  207. Blasius TL, Cai D, Jih GT, Toret CP, Verhey KJ . Two binding partners cooperate to activate the molecular motor Kinesin-1. J Cell Biol 2007; 176: 11–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  208. Koga M, Ishiguro H, Horiuchi Y, Albalushi T, Inada T, Iwata N et al. Failure to confirm the association between the FEZ1 gene and schizophrenia in a Japanese population. Neurosci Lett 2007; 417: 326–329.

    Article  CAS  PubMed  Google Scholar 

  209. Hodgkinson CA, Goldman D, Ducci F, DeRosse P, Caycedo DA, Newman ER et al. The FEZ1 gene shows no association to schizophrenia in Caucasian or African American populations. Neuropsychopharmacology 2007; 32: 190–196.

    Article  CAS  PubMed  Google Scholar 

  210. Yamada K, Nakamura K, Minabe Y, Iwayama-Shigeno Y, Takao H, Toyota T et al. Association analysis of FEZ1 variants with schizophrenia in Japanese cohorts. Biol Psychiatry 2004; 56: 683–690.

    Article  CAS  PubMed  Google Scholar 

  211. Talukder AH, Vadlamudi R, Mandal M, Kumar R . Heregulin induces expression, DNA binding activity, and transactivating functions of basic leucine zipper activating transcription factor 4. Cancer Res 2000; 60: 276–281.

    CAS  PubMed  Google Scholar 

  212. Ritter B, Zschuntsch J, Kvachnina E, Zhang W, Ponimaskin EG . The GABA(B) receptor subunits R1 and R2 interact differentially with the activation transcription factor ATF4 in mouse brain during the postnatal development. Brain Res Dev Brain Res 2004; 149: 73–77.

    Article  CAS  PubMed  Google Scholar 

  213. White JH, McIllhinney RA, Wise A, Ciruela F, Chan WY, Emson PC et al. The GABAB receptor interacts directly with the related transcription factors CREB2 and ATFx. Proc Natl Acad Sci USA 2000; 97: 13967–13972.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  214. Nehring RB, Horikawa HP, El Far O, Kneussel M, Brandstatter JH, Stamm S et al. The metabotropic GABAB receptor directly interacts with the activating transcription factor 4. J Biol Chem 2000; 275: 35185–35191.

    Article  CAS  PubMed  Google Scholar 

  215. Vernon E, Meyer G, Pickard L, Dev K, Molnar E, Collingridge GL et al. GABA(B) receptors couple directly to the transcription factor ATF4. Mol Cell Neurosci 2001; 17: 637–645.

    Article  CAS  PubMed  Google Scholar 

  216. Steiger JL, Bandyopadhyay S, Farb DH, Russek SJ . cAMP response element-binding protein, activating transcription factor-4, and upstream stimulatory factor differentially control hippocampal GABABR1a and GABABR1b subunit gene expression through alternative promoters. J Neurosci 2004; 24: 6115–6126.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  217. Abel T, Martin KC, Bartsch D, Kandel ER . Memory suppressor genes: inhibitory constraints on the storage of long-term memory. Science 1998; 279: 338–341.

    Article  CAS  PubMed  Google Scholar 

  218. Chen A, Muzzio IA, Malleret G, Bartsch D, Verbitsky M, Pavlidis P et al. Inducible enhancement of memory storage and synaptic plasticity in transgenic mice expressing an inhibitor of ATF4 (CREB-2) and C/EBP proteins. Neuron 2003; 39: 655–669.

    Article  CAS  PubMed  Google Scholar 

  219. Angelastro JM, Ignatova TN, Kukekov VG, Steindler DA, Stengren GB, Mendelsohn C et al. Regulated expression of ATF5 is required for the progression of neural progenitor cells to neurons. J Neurosci 2003; 23: 4590–4600.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  220. Angelastro JM, Mason JL, Ignatova TN, Kukekov VG, Stengren GB, Goldman JE et al. Downregulation of activating transcription factor 5 is required for differentiation of neural progenitor cells into astrocytes. J Neurosci 2005; 25: 3889–3899.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  221. Mason JL, Angelastro JM, Ignatova TN, Kukekov VG, Lin G, Greene LA et al. ATF5 regulates the proliferation and differentiation of oligodendrocytes. Mol Cell Neurosci 2005; 29: 372–380.

    Article  CAS  PubMed  Google Scholar 

  222. Kakiuchi C, Iwamoto K, Ishiwata M, Bundo M, Kasahara T, Kusumi I et al. Impaired feedback regulation of XBP1 as a genetic risk factor for bipolar disorder. Nat Genet 2003; 35: 171–175.

    Article  CAS  PubMed  Google Scholar 

  223. Rutkowski DT, Kaufman RJ . All roads lead to ATF4. Dev Cell 2003; 4: 442–444.

    Article  CAS  PubMed  Google Scholar 

  224. Al Sarraj J, Vinson C, Thiel G . Regulation of asparagine synthetase gene transcription by the basic region leucine zipper transcription factors ATF5 and CHOP. Biol Chem 2005; 386: 873–879.

    Article  CAS  PubMed  Google Scholar 

  225. Watatani Y, Kimura N, Shimizu YI, Akiyama I, Tonaki D, Hirose H et al. Amino acid limitation induces expression of ATF5 mRNA at the post-transcriptional level. Life Sci 2007; 80: 879–885.

    Article  CAS  PubMed  Google Scholar 

  226. Kakiuchi C, Ishiwata M, Nanko S, Kunugi H, Minabe Y, Nakamura K et al. Association analysis of ATF4 and ATF5, genes for interacting-proteins of DISC1, in bipolar disorder. Neurosci Lett 2007; 417: 316–321.

    Article  CAS  PubMed  Google Scholar 

  227. Halpain S, Dehmelt L . The MAP1 family of microtubule-associated proteins. Genome Biol 2006; 7: 224.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  228. Fukuyama R, Rapoport SI . Brain-specific expression of human microtubule-associated protein 1A (MAP1A) gene and its assignment to human chromosome 15. J Neurosci Res 1995; 40: 820–825.

    Article  CAS  PubMed  Google Scholar 

  229. Fink JK, Jones SM, Esposito C, Wilkowski J . Human microtubule-associated protein 1a (MAP1A) gene: genomic organization, cDNA sequence, and developmental- and tissue-specific expression. Genomics 1996; 35: 577–585.

    Article  CAS  PubMed  Google Scholar 

  230. Pedrotti B, Colombo R, Islam K . Microtubule associated protein MAP1A is an actin-binding and crosslinking protein. Cell Motil Cytoskeleton 1994; 29: 110–116.

    Article  CAS  PubMed  Google Scholar 

  231. Reese ML, Dakoji S, Bredt DS, Dotsch V . The guanylate kinase domain of the MAGUK PSD-95 binds dynamically to a conserved motif in MAP1a. Nat Struct Mol Biol 2007; 14: 155–163.

    Article  CAS  PubMed  Google Scholar 

  232. Hirohashi Y, Wang Q, Liu Q, Li B, Du X, Zhang H et al. Centrosomal proteins Nde1 and Su48 form a complex regulated by phosphorylation. Oncogene 2006; 25: 6048–6055.

    Article  CAS  PubMed  Google Scholar 

  233. Lauritsen M, Mors O, Mortensen PB, Ewald H . Infantile autism and associated autosomal chromosome abnormalities: a register-based study and a literature survey. J Child Psychol Psychiatry 1999; 40: 335–345.

    Article  CAS  PubMed  Google Scholar 

  234. Liu J, Juo SH, Dewan A, Grunn A, Tong X, Brito M et al. Evidence for a putative bipolar disorder locus on 2p13–16 and other potential loci on 4q31, 7q34, 8q13, 9q31, 10q21–24, 13q32, 14q21 and 17q11–12. Mol Psychiatry 2003; 8: 333–342.

    Article  CAS  PubMed  Google Scholar 

  235. Marcheco-Teruel B, Flint TJ, Wikman FP, Torralbas M, Gonzalez L, Blanco L et al. A genome-wide linkage search for bipolar disorder susceptibility loci in a large and complex pedigree from the eastern part of Cuba. Am J Med Genet B Neuropsychiatr Genet 2006; 141: 833–843.

    Article  Google Scholar 

  236. Segurado R, Detera-Wadleigh SD, Levinson DF, Lewis CM, Gill M, Nurnberger Jr JI et al. Genome scan meta-analysis of schizophrenia and bipolar disorder, part III: Bipolar disorder. Am J Hum Genet 2003; 73: 49–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  237. Tastemir D, Demirhan O, Sertdemir Y . Chromosomal fragile site expression in Turkish psychiatric patients. Psychiatry Res 2006; 144: 197–203.

    Article  CAS  PubMed  Google Scholar 

  238. Britsch S . The neuregulin-I/ErbB signaling system in development and disease. Adv Anat Embryol Cell Biol 2007; 190: 1–65.

    Article  PubMed  Google Scholar 

  239. Mattick JS, Gagen MJ . The evolution of controlled multitasked gene networks: the role of introns and other noncoding RNAs in the development of complex organisms. Mol Biol Evol 2001; 18: 1611–1630.

    Article  CAS  PubMed  Google Scholar 

  240. Vanhee-Brossollet C, Vaquero C . Do natural antisense transcripts make sense in eukaryotes? Gene 1998; 211: 1–9.

    Article  CAS  PubMed  Google Scholar 

  241. Munroe SH, Zhu J . Overlapping transcripts, double-stranded RNA and antisense regulation: a genomic perspective. Cell Mol Life Sci 2006; 63: 2102–2118.

    Article  CAS  PubMed  Google Scholar 

  242. Kumar M, Carmichael GG . Antisense RNA: function and fate of duplex RNA in cells of higher eukaryotes. Microbiol Mol Biol Rev 1998; 62: 1415–1434.

    CAS  PubMed  PubMed Central  Google Scholar 

  243. Costa FF . Non-coding RNAs: new players in eukaryotic biology. Gene 2005; 357: 83–94.

    Article  CAS  PubMed  Google Scholar 

  244. Nishimura Y, Martin CL, Vazquez-Lopez A, Spence SJ, Alvarez-Retuerto AI, Sigman M et al. Genome-wide expression profiling of lymphoblastoid cell lines distinguishes different forms of autism and reveals shared pathways. Hum Mol Genet 2007; 16: 1682–1698.

    Article  CAS  PubMed  Google Scholar 

  245. Group THsDCR. A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes. The Huntington's Disease Collaborative Research Group. Cell 1993; 72: 971–983.

    Article  Google Scholar 

  246. Li SH, Li XJ . Huntingtin and its role in neuronal degeneration. Neuroscientist 2004; 10: 467–475.

    Article  CAS  PubMed  Google Scholar 

  247. Duan X, Chang JH, Ge S, Faulkner RL, Kim JY, Kitabatake Y et al. Disrupted-In-Schizophrenia 1 regulates integration of newly generated neurons in the adult brain. Cell 2007; 130: 1–13.

    Article  CAS  Google Scholar 

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Acknowledgements

We thank Pippa Thomson, Christoph Grunewald and Fumiaki Ogawa for critical reading of this manuscript, and Simon Cooper for creating many of the figures. We regret that much interesting research into DISC1 protein interactors has not been cited or cited only in review form as it was beyond the scope of the current review. We are supported by the Medical Research Council and JKM is a Research Councils UK fellow.

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  1. Medical Genetics Section, The Centre for Molecular Medicine, Western General Hospital, The University of Edinburgh, Edinburgh, UK

    J E Chubb, N J Bradshaw, D C Soares, D J Porteous & J K Millar

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  1. J E Chubb
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The generation and integration of new neurons in the adult hippocampus is an important form of structural plasticity in the mammalian brain. Strikingly, in a recent paper in cell, Duan et al.247 have identified Disc1 as an important mediator of neuronal integration in the adult hippocampus. The authors used stereotaxic surgery to inject retroviral vectors coexpressing GFP and Disci shRNA into proliferating neural progenitor cells in the adult mouse hippocampus. While there was no effect on neuronal fate specification of adult neuronal progenitors, it was demonstrated that Disc1 knockdown results in overextended migration of newborn neurons, soma hypertrophy, increased dendritic initiation and arborization, increased synapse formation and abnormal electrophysiological properties, suggestive of accelerated maturation of these neurons. Complimentary experiments on Ndel1 knockdown suggest that Disc1 and Ndel1 interact synergistically to control the processes of migration and integration of adult-born neurons in the mouse hippocampus.

These data demonstrate that Disc1 may have complex alternative functions during embryonic and adult brain development and maturation, as it has been previously reported by Kamiya et al.66 that knock-down of Disc1 during embryonic brain development in mouse inhibits neuronal migration and dendritic arborization in the developing cortex, while the opposite occurs during adult neurogenesis.

The hippocampus and hippocampal neurogenesis are strongly implicated in schizophrenia and depression, and in the therapeutic action of many drugs used to treat depression. This study by Duan et al.,247 therefore gives us new insight into the mechanisms by which Disc1 might increase susceptibility to psychiatric illness and may also help to explain the adult onset of schizophrenia and related conditions.

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Chubb, J., Bradshaw, N., Soares, D. et al. The DISC locus in psychiatric illness. Mol Psychiatry 13, 36–64 (2008). https://doi.org/10.1038/sj.mp.4002106

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