Human Molecular Genetics, 2003, Vol. 12, No. 13 1591-1608
DOI: 10.1093/hmg/ddg162
© 2003 Oxford University Press
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
Department of Neuroscience, Merck Research Laboratories, West Point, PA 19486, USA
Received March 9, 2003; Revised April 13, 2003; Accepted April 28, 2003
Disrupted-In-Schizophrenia 1 (DISC1) is a novel gene associated with schizophrenia by multiple genetic studies. In order to determine how mutations in DISC1 might cause susceptibility to schizophrenia, we undertook a comprehensive study of the cellular biology of DISC1 in its full-length and disease-associated mutant forms. DISC1 interacts by yeast two-hybrid, mammalian two-hybrid, and co-immunoprecipitation assays with multiple proteins of the centrosome and cytoskeletal system, including MIPT3, MAP1A and NUDEL; proteins which localize receptors to membranes, including 
-actinin2 and ß4-spectrin; and proteins which transduce signals from membrane receptors, including ATF4 and ATF5. Truncated mutant DISC1 fails to interact with ATF4, ATF5 or NUDEL. Deletion mapping demonstrated that DISC1 has distinct interaction domains: MAP1A interacts via its LC2 domain with the N-terminus of DISC1, whereas MIPT3 and NUDEL bind via their C-terminal domains to the central coiled-coil domain of DISC1, and ATF4/5 bind via their C-terminal domains to the C-terminus of DISC1. In its full-length form, DISC1 protein localizes to predominantly perinuclear punctate structures which extend into neurites in some cells; mutant truncated DISC1, by contrast, is seen in a diffuse pattern throughout the cytoplasm and abundantly in neurites. Both forms co-localize with the centrosomal complex, although truncated less abundantly than full-length DISC1. Although both full-length and mutant DISC1 are found in microtubule fractions, neither form of DISC1 appears to bind directly to microtubules, but rather do so in a MIPT3-dependent fashion that is stabilized by taxol. Based on these data, we propose that DISC1 is a multifunctional protein whose truncation contributes to schizophrenia susceptibility by disrupting intracellular transport, neurite architecture and/or neuronal migration, all of which have been hypothesized to be pathogenic in the schizophrenic brain.
* To whom correspondence should be addressed at: National Human Genome Research Institute, National Institutes of Health, Building 31, Room 4B09, 31 Center Drive, Bethesda, MD 20892, USA. Tel: +1 3015946238; Fax: +1 3014020837; Email: austinc{at}mail.nih.gov
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  K. E. Burdick, A. Kamiya, C. A. Hodgkinson, T. Lencz, P. DeRosse, K. Ishizuka, S. Elashvili, H. Arai, D. Goldman, A. Sawa, et al. Elucidating the relationship between DISC1, NDEL1 and NDE1 and the risk for schizophrenia: Evidence of epistasis and competitive binding Hum. Mol. Genet., August 15, 2008; 17(16): 2462 - 2473. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Kvajo, H. McKellar, P. A. Arguello, L. J. Drew, H. Moore, A. B. MacDermott, M. Karayiorgou, and J. A. Gogos A mutation in mouse Disc1 that models a schizophrenia risk allele leads to specific alterations in neuronal architecture and cognition PNAS, May 13, 2008; 105(19): 7076 - 7081. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Y. Shim, B. A. Samuels, J. Wang, G. Neumayer, C. Belzil, R. Ayala, Y. Shi, Y. Shi, L.-H. Tsai, and M. D. Nguyen Ndel1 Controls the Dynein-mediated Transport of Vimentin during Neurite Outgrowth J. Biol. Chem., May 2, 2008; 283(18): 12232 - 12240. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. Lajoie-Mazenc, D. Tovar, M. Penary, B. Lortal, S. Allart, C. Favard, M. Brihoum, A. Pradines, and G. Favre MAP1A Light Chain-2 Interacts with GTP-RhoB to Control Epidermal Growth Factor (EGF)-dependent EGF Receptor Signaling J. Biol. Chem., February 15, 2008; 283(7): 4155 - 4164. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Bacaj, Y. Lu, and S. Shaham The Conserved Proteins CHE-12 and DYF-11 Are Required for Sensory Cilium Function in Caenorhabditis elegans Genetics, February 1, 2008; 178(2): 989 - 1002. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Li, Y. Zhou, J. D. Jentsch, R. A. M. Brown, X. Tian, D. Ehninger, W. Hennah, L. Peltonen, J. Lonnqvist, M. O. Huttunen, et al. Specific developmental disruption of disrupted-in-schizophrenia-1 function results in schizophrenia-related phenotypes in mice PNAS, November 13, 2007; 104(46): 18280 - 18285. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
O. M. Palo, M. Antila, K. Silander, W. Hennah, H. Kilpinen, P. Soronen, A. Tuulio-Henriksson, T. Kieseppa, T. Partonen, J. Lonnqvist, et al. Association of distinct allelic haplotypes of DISC1 with psychotic and bipolar spectrum disorders and with underlying cognitive impairments Hum. Mol. Genet., October 15, 2007; 16(20): 2517 - 2528. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Murdoch, S. Mackie, D. M. Collins, E. V. Hill, G. B. Bolger, E. Klussmann, D. J. Porteous, J. K. Millar, and M. D. Houslay Isoform-Selective Susceptibility of DISC1/Phosphodiesterase-4 Complexes to Dissociation by Elevated Intracellular cAMP Levels J. Neurosci., August 29, 2007; 27(35): 9513 - 9524. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Shinoda, S. Taya, D. Tsuboi, T. Hikita, R. Matsuzawa, S. Kuroda, A. Iwamatsu, and K. Kaibuchi DISC1 Regulates Neurotrophin-Induced Axon Elongation via Interaction with Grb2 J. Neurosci., January 3, 2007; 27(1): 4 - 14. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Taya, T. Shinoda, D. Tsuboi, J. Asaki, K. Nagai, T. Hikita, S. Kuroda, K. Kuroda, M. Shimizu, S. Hirotsune, et al. DISC1 Regulates the Transport of the NUDEL/LIS1/14-3-3{varepsilon} Complex through Kinesin-1 J. Neurosci., January 3, 2007; 27(1): 15 - 26. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. C. Roberts Schizophrenia in Translation: Disrupted in Schizophrenia (DISC1): Integrating Clinical and Basic Findings Schizophr Bull, January 1, 2007; 33(1): 11 - 15. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Kamiya, T. Tomoda, J. Chang, M. Takaki, C. Zhan, M. Morita, M. B. Cascio, S. Elashvili, H. Koizumi, Y. Takanezawa, et al. DISC1-NDEL1/NUDEL protein interaction, an essential component for neurite outgrowth, is modulated by genetic variations of DISC1 Hum. Mol. Genet., November 15, 2006; 15(22): 3313 - 3323. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Hashimoto, T. Numakawa, T. Ohnishi, E. Kumamaru, Y. Yagasaki, T. Ishimoto, T. Mori, K. Nemoto, N. Adachi, A. Izumi, et al. Impact of the DISC1 Ser704Cys polymorphism on risk for major depression, brain morphology and ERK signaling Hum. Mol. Genet., October 15, 2006; 15(20): 3024 - 3033. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Hennah, P. Thomson, L. Peltonen, and D. Porteous Genes and Schizophrenia: Beyond Schizophrenia: The Role of DISC1 in Major Mental Illness Schizophr Bull, July 1, 2006; 32(3): 409 - 416. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Nakatani, E. Hattori, T. Ohnishi, B. Dean, Y. Iwayama, I. Matsumoto, T. Kato, N. Osumi, T. Higuchi, S.-I. Niwa, et al. Genome-wide expression analysis detects eight genes with robust alterations specific to bipolar I disorder: relevance to neuronal network perturbation Hum. Mol. Genet., June 15, 2006; 15(12): 1949 - 1962. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. B. Vallee and J.-W. Tsai The cellular roles of the lissencephaly gene LIS1, and what they tell us about brain development Genes & Dev., June 1, 2006; 20(11): 1384 - 1393. [Full Text] [PDF]
|
|
|
|
|
|
B. K. Lipska, T. Peters, T. M. Hyde, N. Halim, C. Horowitz, S. Mitkus, C. S. Weickert, M. Matsumoto, A. Sawa, R. E. Straub, et al. Expression of DISC1 binding partners is reduced in schizophrenia and associated with DISC1 SNPs Hum. Mol. Genet., April 15, 2006; 15(8): 1245 - 1258. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. D. Cannon, W. Hennah, T. G. M. van Erp, P. M. Thompson, J. Lonnqvist, M. Huttunen, T. Gasperoni, A. Tuulio-Henriksson, T. Pirkola, A. W. Toga, et al. Association of DISC1/TRAX Haplotypes With Schizophrenia, Reduced Prefrontal Gray Matter, and Impaired Short- and Long-term Memory Arch Gen Psychiatry, November 1, 2005; 62(11): 1205 - 1213. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. H. Callicott, R. E. Straub, L. Pezawas, M. F. Egan, V. S. Mattay, A. R. Hariri, B. A. Verchinski, A. Meyer-Lindenberg, R. Balkissoon, B. Kolachana, et al. Variation in DISC1 affects hippocampal structure and function and increases risk for schizophrenia PNAS, June 14, 2005; 102(24): 8627 - 8632. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. A. F. Hayashi, F. C. V. Portaro, M. F. Bastos, J. R. Guerreiro, V. Oliveira, S. S. Gorrao, D. V. Tambourgi, O. A. Sant'Anna, P. J. Whiting, L. M. Camargo, et al. Inhibition of NUDEL (nuclear distribution element-like)-oligopeptidase activity by disrupted-in-schizophrenia 1 PNAS, March 8, 2005; 102(10): 3828 - 3833. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Lee, C. L. Walker, B. Karten, S. L. Kuny, A. A. Tennese, M. A. O'Neill, and R. Wevrick Essential role for the Prader-Willi syndrome protein necdin in axonal outgrowth Hum. Mol. Genet., March 1, 2005; 14(5): 627 - 637. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Sawamura, T. Sawamura-Yamamoto, Y. Ozeki, C. A. Ross, and A. Sawa A form of DISC1 enriched in nucleus: Altered subcellular distribution in orbitofrontal cortex in psychosis and substance/alcohol abuse PNAS, January 25, 2005; 102(4): 1187 - 1192. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. H. Ives, S. Fung, P. Tiwari, H. L. Payne, and C. L. Thompson Microtubule-associated Protein Light Chain 2 Is a Stargazin-AMPA Receptor Complex-interacting Protein in Vivo J. Biol. Chem., July 23, 2004; 279(30): 31002 - 31009. [Abstract] [Full Text] [PDF]
|
|