In this paper, Lee et al. characterized DISC1 mutant mice, animals with ENU-induced mutation of Q31L and L100P, by systematic histological examinations. These animals had been previously reported to show behavioral abnormalities relevant to major mental disorders, such as schizophrenia and major depression, by Roder and Clapcote (Clapcote et al., 2007). The authors found decreased cell proliferation, altered neuronal distribution, as well as impaired dendritic growth and reduction of spine density in pyramidal neurons, all phenotypes observed in the cerebral cortex. As the authors described, these abnormal cellular architectures had been previously reported in the other DISC1 animal models, including studies using RNAi approaches (Kamiya et al., 2005; Li et al., 2007; Kvajo et al., 2008; Pletnikov et al., 2008; Shen et al., 2008; Mao et al., 2009; Hayashi-Takagi et al., 2010; Niwa et al., 2010). An important question arising is whether all DISC1 functions in such cellular events are implicated in disease processes or some specific functional aspects are critical. This is a tremendously difficult question, because the molecular disposition of DISC1 is complex, as reflected by multiple isoforms at both mRNA and protein levels (Nakata et al., 2009; Ishizuka et al., 2006). Nonetheless, biological functions of DISC1 are currently being explored without waiting for the complete identification of DISC1 isoforms, resulting in the identification of multiple roles of DISC1 with many protein interactors in various functional contexts. Further investigations with advanced genetic engineering techniques, which allow researchers to dissect region and cell type-specific DISC1 functions in a temporal manner, might allow us to more clearly elucidate DISC1 functions relevant to psychiatric disorders.
Clapcote SJ, Lipina TV, Millar JK, Mackie S, Christie S, Ogawa F, Lerch JP, Trimble K, Uchiyama M, Sakuraba Y, Kaneda H, Shiroishi T, Houslay MD, Henkelman RM, Sled JG, Gondo Y, Porteous DJ, Roder JC. Behavioral phenotypes of Disc1 missense mutations in mice. Neuron. 2007 May 3;54(3):387-402. Abstract
Kamiya A, Kubo K, Tomoda T, Takaki M, Youn R, Ozeki Y, Sawamura N, Park U, Kudo C, Okawa M, Ross CA, Hatten ME, Nakajima K, Sawa A. A schizophrenia-associated mutation of DISC1 perturbs cerebral cortex development. Nat Cell Biol. 2005 Dec;7(12):1167-78. Epub 2005 Nov 20. Erratum in: Nat Cell Biol. 2006 Jan;8(1):100. Abstract
Li W, Zhou Y, Jentsch JD, Brown RA, Tian X, Ehninger D, Hennah W, Peltonen L, Lönnqvist J, Huttunen MO, Kaprio J, Trachtenberg JT, Silva AJ, Cannon TD. Specific developmental disruption of disrupted-in-schizophrenia-1 function results in schizophrenia-related phenotypes in mice. Proc Natl Acad Sci U S A. 2007 Nov 13;104(46):18280-5. Epub 2007 Nov 2. Abstract
Kvajo M, McKellar H, Arguello PA, Drew LJ, Moore H, MacDermott AB, Karayiorgou M, Gogos JA. A mutation in mouse Disc1 that models a schizophrenia risk allele leads to specific alterations in neuronal architecture and cognition. Proc Natl Acad Sci U S A. 2008 May 13;105(19):7076-81. Epub 2008 May 5. Abstract
Pletnikov MV, Ayhan Y, Nikolskaia O, Xu Y, Ovanesov MV, Huang H, Mori S, Moran TH, Ross CA. Mol Psychiatry. 2008 Feb;13(2):173-86, 115. Inducible expression of mutant human DISC1 in mice is associated with brain and behavioral abnormalities reminiscent of schizophrenia. Epub 2007 Sep 11. Abstract
Shen S, Lang B, Nakamoto C, Zhang F, Pu J, Kuan SL, Chatzi C, He S, Mackie I, Brandon NJ, Marquis KL, Day M, Hurko O, McCaig CD, Riedel G, St Clair D. Schizophrenia-related neural and behavioral phenotypes in transgenic mice expressing truncated Disc1. J Neurosci. 2008 Oct 22;28(43):10893-904. Abstract
Mao Y, Ge X, Frank CL, Madison JM, Koehler AN, Doud MK, Tassa C, Berry EM, Soda T, Singh KK, Biechele T, Petryshen TL, Moon RT, Haggarty SJ, Tsai LH. Disrupted in schizophrenia 1 regulates neuronal progenitor proliferation via modulation of GSK3beta/beta-catenin signaling. Cell. 2009 Mar 20;136(6):1017-31. Abstract
Hayashi-Takagi A, Takaki M, Graziane N, Seshadri S, Murdoch H, Dunlop AJ, Makino Y, Seshadri AJ, Ishizuka K, Srivastava DP, Xie Z, Baraban JM, Houslay MD, Tomoda T, Brandon NJ, Kamiya A, Yan Z, Penzes P, Sawa A. Disrupted-in-Schizophrenia 1 (DISC1) regulates spines of the glutamate synapse via Rac1. Nat Neurosci. 2010 Mar;13(3):327-32. Epub 2010 Feb 7. Abstract
Niwa M, Kamiya A, Murai R, Kubo K, Gruber AJ, Tomita K, Lu L, Tomisato S, Jaaro-Peled H, Seshadri S, Hiyama H, Huang B, Kohda K, Noda Y, O'Donnell P, Nakajima K, Sawa A, Nabeshima T. Knockdown of DISC1 by in utero gene transfer disturbs postnatal dopaminergic maturation in the frontal cortex and leads to adult behavioral deficits. Neuron. 2010 Feb 25;65(4):480-9. Abstract
Nakata K, Lipska BK, Hyde TM, Ye T, Newburn EN, Morita Y, Vakkalanka R, Barenboim M, Sei Y, Weinberger DR, Kleinman JE. DISC1 splice variants are upregulated in schizophrenia and associated with risk polymorphisms. Proc Natl Acad Sci U S A. 2009 Sep 15;106(37):15873-8. Epub 2009 Sep 2. Abstract
Ishizuka K, Paek M, Kamiya A, Sawa A. A review of Disrupted-In-Schizophrenia-1 (DISC1): neurodevelopment, cognition, and mental conditions. Biol Psychiatry. 2006 Jun 15;59(12):1189-97. Abstract
View all comments by Atsushi Kamiya
This recent and important paper by Sawa's group adds another layer to the complex story of DISC1 function in neurodevelopment. Their findings clarify and integrate two streams of research implicating DISC1 in both neuron proliferation and migration. The identification of the S170 phosphorylation site also raises the exciting possibility that pharmacological strategies targeted at this phosphorylation-dependent switch might be useful in correcting or preventing mental illness-related problems with brain development. It would be interesting in this context to explore whether disease-associated DISC1 gene variants in humans affect DISC1 phosphorylation, and the subsequent balance between neuron proliferation and migration.
I agree with Atsushi Kamiya that further work is needed to understand which of the many effects of DISC1 perturbation are specific to human psychiatric disease phenotypes. Again, from a treatment perspective, it is vital to know which cellular abnormality underlies the most debilitating symptoms so that new treatments can be screened for effects on these specific abnormalities. Another recent paper from our group reinforces this point (Lee et al., 2011). We found that genetic inactivation of GSK3α restored dendritic spine deficits in DISC1 L100P mutant mice, in parallel with amelioration of behavioral abnormalities as previously reported (Lipina et al., 2011). However, other abnormalities in dendrite morphology caused by the DISC1 L100P mutation were not corrected by GSK3α inactivation.
Lee FH, Kaidanovich-Beilin O, Roder JC, Woodgett JR, Wong AH. Genetic inactivation of GSK3α rescues spine deficits in Disc1-L100P mutant mice, Schizophrenia Research. 2011;Apr 16. Abstract
Lipina TV, Kaidanovich-Beilin O, Patel S, Wang M, Clapcote SJ, Liu F, Woodgett JR, Roder JC. Genetic and pharmacological evidence for schizophrenia-related Disc1 interaction with GSK-3. Synapse. 2011;65:234-248. AbstractView all comments by Albert H. C. Wong