Schizophrenia Research Forum - A Catalyst for Creative Thinking

Messing with DISC1 Protein Disturbs Development, and More

20 November 2005. When it rains, it pours, they say, and that may be the case with two major papers, appearing in rapid succession and unleashing a torrent of new information about the role of the DISC1 gene in mental illness. DISC1 (disrupted in schizophrenia 1) has been identified in several families with schizophrenia and other major mental disorders, but just how mutations in this gene precipitate illness is unclear. A new report from Kirsty Millar, David Porteous, and colleagues in Science reveals that DISC1 partners with phosphodiesterase 4B, an enzyme that regulates levels of cAMP in neurons. This link between DISC1 and the cAMP signaling pathway, which functions in cognition, memory, and mood, could help explain how the altered genes can elicit psychiatric symptoms via faulty neurotransmitter signaling.

The pathogenesis of schizophrenia has a developmental component as well, and in another paper, Akira Sawa and colleagues from the US and Japan explore the impact of the DISC1 translocation on brain development. Writing in Nature Cell Biology, the group reports that a carboxy-terminal truncated form of DISC1 disrupts neuronal migration and axon growth by destabilizing the dynein motor and disrupting microtubule dynamics. Their work explains how the translocation involving DISC1 could contribute to the changes in neural architecture that have been reported in the brains of people with schizophrenia.

It was a rearranged chromosome in a large Scottish family with frequent mental illness that led Porteous and colleagues to DISC1 several years ago (Millar et al., 2000). In their new paper, Millar and collaborators in Edinburgh, Glasgow, France, and the UK report the discovery of a different rearrangement in another person with schizophrenia that disrupts two genes, phosphodiesterase 4B (PDE4B) and cadherin 8. Of the two, they chose to focus on PDE4B, an enzyme which degrades and inactivates the second messenger cAMP. They showed that expression of PDE4B was decreased in the patient with the translocation. Add to that a previous observation (Brandon et al., 2004) that DISC1 and PDE4B interact in a two-hybrid screen, and the researchers were off and running, looking for a link between the two proteins in cells.

Several approaches established that DISC1 and PDE4B were directly physically associated in neurons. Standard coexpression and coimmunoprecipitation experiments revealed that multiple isoforms of PDE4B directly interacted with the N-terminal end of DISC1. The endogenous PDE4B1 isoform coprecipitated with a 71 kDa form of DISC1. Cell fractionation showed that both of the proteins were most abundant in the mitochondria-enriched fraction, and fluorescence microscopy revealed an overlapping distribution in that compartment.

PDE4B enzyme activity is increased by elevation of cAMP and activation of PKA, which phosphorylates a regulatory domain on PDE4B. Using pharmacological elevators of cAMP, Millar and coworkers showed that increasing cAMP caused a decrease in the association of PDE4B with DISC1, and this effect required PKA activity. Their results support the idea that DISC1 binds a dephosphorylated, inactive form of PDE4B. When cAMP levels go up, PDE4B becomes phosphorylated and active, and the proteins dissociate. Having shown that chromosomal translocations involving PDE4B or DISC1 decreased expression of their respective proteins by about half, and that the interaction between the two proteins is dynamic, the authors conclude by speculating that “functional variation in DISC1 and/or PDE4 will modulate their interaction and affect mitochondrial cAMP catabolism with a concomitant physiological and psychiatric outcome.”

In a perspective piece in the same issue of Science, Sawa and Solomon Snyder from Johns Hopkins ask whether PDE4B presents a new therapeutic target for schizophrenia. If DISC1 deficiency results in higher PDE4 activity, it would make sense to look for agents that increase binding of DISC1 to PDE4B, or even direct inhibitors of the enzyme, like the antidepressant rolipram (see SRF related news story). But, they point out, it’s hard to predict the effects of elevating cAMP, which serves different functions in different areas of the brain. Nonetheless, they conclude that the work provides a unifying link between schizophrenia and mood disorders, which often occur in the same families, and sometimes in the same individuals, as in schizoaffective disorder.

In his paper in Nature Cell Biology, Sawa has another story to tell about DISC1 and its role in neurodevelopment. In this study, first author Atsushi Kamiya and coworkers show that DISC1 is part of the dynein motor complex, along with the developmentally important proteins NUDEL and LIS1, and stabilizes the complex at the centrosome, contributing to normal microtubule dynamics. The carboxy-terminal truncation of DISC1 that occurs in the Scottish family acts like a dominant negative, knocking normal DISC1 out of the dynein complex and impairing motor activity.

In neurons, the dynein motor and its effects on microtubule organization help drive neuronal migration and axon formation during development. When the researchers used RNAi to lower DISC1 expression in neurons in culture, or expressed the truncated DISC1, they observed decreased neurite outgrowth. Moving in vivo, they performed in utero electroporation to deliver RNAi or mutated DISC1 to fetal rat cortical neurons, and showed decreased migration of neurons during cortical development. Neurons that did make it to their correct positions had impaired orientation, polarity, and dendritic arborization. While nearly complete knockdown of DISC1 with a potent RNAi caused almost full inhibition of migration, the mutant DISC1 produced a partial migration defect, consistent with the subtle developmental changes seen in brains of schizophrenic patients.

Whether the DISC1 gene translocation in people results in a deficiency of protein, or the production of a mutant protein, or both, is still an open question, but either could account for what Sawa and colleagues propose to be a key developmental impairment resulting from a loss of DISC1 function. Importantly, both the PDE4 and dynein connections for DISC1 allow for dose-dependent partial effects that could produce a spectrum of disorders, with various combinations of schizophrenic and affective symptoms, stemming from both developmental and functional roots.—Pat McCaffrey.

Millar JK, Pickard BS, Mackie S, James R, Christie S, Buchanan SR, Malloy MP, Chubb JE, Huston E, Baillie GS, Thomson PA, Hill EV, Brandon NJ, Rain JC, Camargo LM, Whiting PJ, Houslay MD, Blackwood DH, Muir WJ, Porteous DJ. DISC1 and PDE4B Are Interacting Genetic Factors in Schizophrenia That Regulate cAMP Signaling. Science. 2005 Nov 18;310:1187-1191. Abstract

Sawa A, Snyder SH. GENETICS: Two Genes Link Two Distinct Psychoses. Science. 2005 Nov 18;310:1128-1129. 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. Nature Cell Biology. 2005 November 20. Advance online publication. Abstract

Comments on News and Primary Papers
Comment by:  Anil Malhotra, SRF Advisor
Submitted 21 November 2005
Posted 21 November 2005

The relationship between DISC1 and neuropsychiatric disorders, including schizophrenia, schizoaffective disorder, and bipolar disorder, has now been observed in several studies. Moreover, a number of studies have demonstrated that DISC1 appears to impact neurocognitive function. Nevertheless, the molecular mechanisms by which DISC1 could contribute to impaired CNS function are unclear, and these two papers shed light on this critical issue.

Millar et al. (2005) have followed the same strategy that they so successfully utilized in their initial DISC1 studies, identifying a translocation that associated with a psychotic illness. In contrast to DISC1, in which a pedigree was identified with a number of translocation carriers, this manuscript is based upon the identification of a single translocation carrier, who appears to manifest classic signs of schizophrenia, without evidence of mood dysregulation. Two genes are disrupted by this translocation: cadherin 8 and phosphodiesterase 4B (PDE4B). The researchers' elegant set of experiments provides compelling biological evidence that PDE4B interacts with DISC1 and suggests a mechanism mediated by cAMP for DISC1/PDE4B effects on basic molecular processes underlying learning, memory, and perhaps psychosis. It remains possible that PDE4B (and DISC1) are proteins fundamentally involved in cognitive processes, and that the observed relationship to psychotic illnesses represents a final common pathway of neurocognitive impairment. This would be consistent with data from our group (Lencz et al., in press) demonstrating that verbal memory impairment specifically predicts onset of psychosis in at-risk subjects. Similarly, Burdick et al. (2005) found that our DISC1 risk genotypes (Hodgkinson et al., 2004) were associated with impaired verbal working memory. Finally, Callicott et al. (2005) found that a DISC1 risk SNP, Ser704Cys, predicted hippocampal dysfunction, an SNP which we (DeRosse et al., unpublished data) have also found to link with the primary psychotic symptoms (persecutory delusions) manifested by the patient in the Millar et al. study. This body of evidence supports the notion that these proteins play fundamental roles in the key clinical manifestations of schizophrenia.

Kamiya et al. (2005) provide another potential mechanism for these effects, suggesting that a DISC1 mutation may disrupt cerebral cortical development, hinting that studies examining the role of DISC1 genotypes on brain structure and function in the at-risk schizophrenia pediatric patients may be fruitful.

Taken together, these papers add considerable new data suggesting that DISC1 plays a key role in the etiology of schizophrenia, and places DISC1 at the forefront of the rapidly growing body of schizophrenia candidate genes.

Burdick KE, Hodgkinson CA, Szeszko PR, Lencz T, Ekholm JM, Kane JM, Goldman D, Malhotra AK. DISC1 and neurocognitive function in schizophrenia. Neuroreport 2005; 16(12):1399-1402. Abstract

Callicott JH, Straub RE, Pezawas L, Egan MF, Mattay VS, Hariri AR, Verchinski BA, Meyer-Lindenberg A, Balkissoon R, Kolachana B, Goldberg TE, Weinberger DR. Variation in DISC1 affects hippocampal structure and function and increases risk for schizophrenia. Proc Natl Acad Sci USA 2005; 102(24): 8627-8632. Abstract

Hodgkinson CA, Goldman D, Jaeger J, Persaud S, Kane JM, Lipsky RH, Malhotra AK. Disrupted in Schizophrenia (DISC1): Association with schizophrenia, schizoaffective disorder, and bipolar disorder. Am J Hum Genet 2004; 75:862-872. Abstract

Lencz T, Smith CW, McLaughlin D, Auther A, Nakayama E, Hovey L, Cornblatt BA. Generalized and specific neurocognitive deficits in prodromal schizophrenia. Biological Psychiatry (in press).

View all comments by Anil Malhotra

Primary Papers: DISC1 and PDE4B are interacting genetic factors in schizophrenia that regulate cAMP signaling.

Comment by:  Robert Peers
Submitted 6 December 2005
Posted 19 December 2005

PDE 4B enzyme activity is increased by PKA activation, hence, the suggested use of PDE inhibitors (like rolipram) in schizophrenia. I have another suggestion, especially because rolipram has unacceptable side-effects. Lauren Marangell's group in Texas (Mirnikjoo et al., 2001) has found that long-chain omega-3 essential fatty acids inhibit several protein kinases, including PKA.

Not only does this observation suggest one mechanism for the suggested benefits of omega-3 treatment of schizophrenia, but it also makes one wonder about the role of dietary omega-3 deficiency in causing or aggravating schizophrenia, especially during gestation, infancy, childhood, and adolescence, when unregulated PDE 4B activity could gravely affect neural development, contributing to schizophrenia pathogenesis.

Such deficiency may have begun, in industrial Western populations, when national fish consumption began to decline during the nineteenth century. Schizophrenia patients—and their mothers—in Western nations tend to eat a diet rich in saturated fats and low in omega-3, and have a worse outcome than in poorer nations, like India and Nigeria, where this dietary pattern is reversed. In 1977, Sartorius and colleagues concluded that the prognosis in schizophrenia, diagnosed by strict criteria, was considerably better in the collaborating centers in poorer nations, especially in India and Nigeria, than in the US, UK, or Denmark (Sartorius, 1977). An important re-analysis of the WHO study was made in 1988, by O and E Christensen in Denmark, who showed that 97 percent of the variance in outcome in the WHO study was explained by diet; in particular, low saturated fat intake combined with essential fatty acids from plant foods and seafood to explain the distinctly better outcome in Agra and Ibadan (Christensen and Christensen, 1988).

It is on this solid basis that some schizophrenia researchers (e.g., Scottish researcher Dr Iain Glen and his colleague Malcolm Peet in Sheffield), aware that dietary fatty acids influence brain membrane composition, are actively pursuing lipid nutrition as the most promising area of diet to improve schizophrenia outcome. Watch this space!

Mirnikjoo B, Brown SE, Kim HF, Marangell LB, Sweatt JD, Weeber EJ. Protein kinase inhibition by omega-3 fatty acids. J Biol Chem. 2001 Apr 6;276(14):10888-96. Epub 2001 Jan 10. Abstract

Sartorius N, Jablensky A, Shapiro R. Two-year follow-up of the patients included in the WHO International Pilot Study of Schizophrenia. Psychol Med. 1977 Aug 1;7(3):529-41. Abstract

Christensen O, Christensen E. Fat consumption and schizophrenia. Acta Psychiatr Scand. 1988 Nov 1;78(5):587-91. Abstract

View all comments by Robert PeersComment by:  Angus Nairn
Submitted 29 December 2005
Posted 31 December 2005
  I recommend the Primary Papers

This study describes an interesting genetic link between PDE4B (phosphodiesterase 4B) and schizophrenia that may be related to a physical interaction with DISC1 (disrupted in schizophrenia 1), another gene associated with the psychiatric disorder. The study is highly suggestive of a role for the PDE4B/DISC1 complex in schizophrenia. However, the mechanistic model suggested by the authors whereby DISC1 sequesters PDE4B in an inactive state seems overly speculative, given the results presented in this paper and in prior studies that have examined the regulation of PDE4B by phosphorylation in the absence of DISC1.

View all comments by Angus NairnComment by:  Patricia Estani
Submitted 2 January 2006
Posted 2 January 2006
  I recommend the Primary Papers

Primary Papers: DISC1 and PDE4B are interacting genetic factors in schizophrenia that regulate cAMP signaling.

Comment by:  Miles Houslay
Submitted 7 January 2006
Posted 7 January 2006
  I recommend this paper

Response to comment by Angus Nairn
Thanks for your comment, Angus. With respect to the model proposed in our paper (Millar et al., 2005), perhaps it wasn't clear enough. However, the model proposed in this study envisages that DISC1 sequesters PDE4B in a "low(er) activity state," and most definitely not in an inactive state. Then it is suggested that activation of PKA by elevated cAMP levels allows, in these differentiated cells, for the release of PKA phosphorylated PDE4B in a "high(er) activity state." Interaction with DISC1 does not affect per se the activity of PDE4B in our hands. PDE4B does not need to be phosphorylated by PKA to be active (see, e.g., MacKenzie et al., 2002).

Note that PDE4 isoforms play a key role in underpinning compartmentalized cAMP signaling through interacting with distinct proteins in cells (Baillie et al., 2005; Baillie and Houslay, 2005; Houslay et al., 2005). It may well be that PDE4B released from DISC1 interacts with other protein(s) in these cells and thereby exerts functional effects. The precedent for this comes from studies on the PDE4D5 isoform, which on release from RACK1 interacts with β-arrestin and regulates β2-adrenoceptor functioning. I trust that this clarifies the situation.

MacKenzie SJ, Baillie GS, McPhee I, MacKenzie C, Seamons R, McSorley T, Millen J, Beard MB, van Heeke G, Houslay MD. Long PDE4 cAMP specific phosphodiesterases are activated by protein kinase A-mediated phosphorylation of a single serine residue in Upstream Conserved Region 1 (UCR1). Br J Pharmacol. 2002 Jun;136(3):421-33. Abstract

Baillie GS, Houslay MD. Arrestin times for compartmentalised cAMP signalling and phosphodiesterase-4 enzymes. Curr Opin Cell Biol. 2005 Apr;17(2):129-34. Review. Abstract

Baillie GS, Scott JD, Houslay MD. Compartmentalisation of phosphodiesterases and protein kinase A: opposites attract. FEBS Lett. 2005 Jun 13;579(15):3264-70. Epub 2005 Apr 14. Review. Abstract

Houslay MD, Schafer P, Zhang KY. Keynote review: phosphodiesterase-4 as a therapeutic target. Drug Discov Today. 2005 Nov 15;10(22):1503-19. Review. Abstract

View all comments by Miles HouslayComment by:  Ali Mohammad Foroughmand
Submitted 16 December 2006
Posted 16 December 2006
  I recommend the Primary Papers

Comments on Related News

Related News: Lis1 Acts as Middleman for Actin and Microtubules

Comment by:  Akira Sawa, SRF Advisor
Submitted 12 January 2006
Posted 12 January 2006

I found the paper by Kholmanskikh and colleagues, which proposes a novel role for LIS1 in neuronal motility by bridging calcium signaling to Cdc42, of great interest for schizophrenia research. LIS1 was originally identified as the causative gene for lissencephaly, but cascades that include LIS1 may have implications for schizophrenia. Several groups, including ours, have reported that a candidate gene product for schizophrenia, DISC1, forms a protein complex with LIS1 (Brandon et al., 2004; Kamiya et al., 2005).

My collaborators, Brian Kirkpatrick and Rosy Roberts, have observed and presented data that DISC1 immunoreactivity is enriched in some (but not all) of the postsynaptic densities, where Rho-family GTPases, such as Cdc42, also occur and regulate synaptic functions (Society for Neuroscience Meeting, 2004). Many of us agree that schizophrenia is, at least in part, a disorder of synapses. Taken all together, it may be useful to have a working hypothesis that a candidate susceptibility gene product for schizophrenia, DISC1, may have an additional role in regulating synaptic functions via Rho-family GTPases, probably in some association with LIS1.

This paper may attract researchers on schizophrenia in another context. The authors used D-serine as a trigger of calcium signaling via activation of the NMDA receptor. Although several genes coding for proteins that are involved in synthesis and degradation of D-serine have been associated with schizophrenia, pathophysiological roles for D-serine remain to be elucidated. In this sense, the impact of D-serine in activation of Cdc42 and synaptic morphology may have implications for schizophrenia research. Personally speaking, it is the most interesting point in this paper that the authors use D-serine in this type of experiment.

View all comments by Akira Sawa

Related News: Nature Makes a DISC1-Deficient, Forgetful Mouse

Comment by:  Anil Malhotra, SRF AdvisorKatherine E. Burdick
Submitted 7 March 2006
Posted 7 March 2006
  I recommend the Primary Papers

The two latest additions to the burgeoning DISC1 literature provide additional support for a role of this gene in cognitive function and schizophrenia, and suggest that more comprehensive studies will be useful as we move to a greater understanding of its role in CNS function. Koike et al. (2006) found that a relatively common mouse strain has a naturally occurring mutation in DISC1 resulting in a truncated form of the protein, similar in size (exon 7 vs. exon 8 disruptions) to that observed in the members of the Scottish pedigree in which the translocation was first detected. C57/BL/6J mice, into which mutant alleles were transferred, displayed significant impairments on a spatial working memory task similar to one used in humans (Lencz et al., 2003). These data are similar to those observed by our group (Burdick et al., 2005) and others (Callicott et al., 2005; Hennah et al., 2005; Cannon et al., 2005), although no study to date has utilized the same neurocognitive tasks. Lipska et al. (2006) report that genes and proteins (NUDEL, FEZ1) known to interact with DISC1 are also aberrant in schizophrenia postmortem tissue, with some evidence that DISC1 risk polymorphisms also influence expression across the pathway.

Taken together, these two papers suggest that the assessment of genes involved in the DISC1 pathway may be worthwhile in the evaluation of working memory function. To date, most studies have focused on risk alleles within DISC1, with little attention paid to the critical interacting genes. Studies are now underway assessing the relationship between FEZ1 and NUDEL and risk for schizophrenia in a number of populations, as well as studies examining their role in neurocognitive and neuroimaging parameters. Clearly, as the Lipska paper indicates, studies that attempt to assess multiple genes in this pathway will be critical, although the common concern of power in assessing gene-gene interactions, especially across multiple genes, may be a limitation. Moreover, these studies indicate that interaction studies will need to consider additional phenotypes other than diagnosis, and perhaps “purer” tasks of neurocognitive function may be worthwhile, as suggested by Koike et al. Finally, both of these papers underscore the fact that the next wave of genetic studies of schizophrenia will encompass the use of multiple probes, whether with neurocognitive assessments, postmortem analyses, or animal models of disease, amongst others, to fully validate the relationships between putative risk genes and the pathophysiology of schizophrenia and related disorders.


Burdick KE, Hodgkinson CA, Szeszko PR, Lencz T, Ekholm JM, Kane JM, Goldman D, Malhotra AK. DISC1 and neurocognitive function in schizophrenia. Neuroreport 2005; 16(12): 1399-1402. Abstract

Callicott JH, Straub RE, Pezawas L, Egan MF, Mattay VS, Hariri AR, Verchinski BA, Meyer-Lindenberg A, Balkissoon R, Kolachana B, Goldberg TE, Weinberger DR. Variation in DISC1 affects hippocampal structure and function and increases risk for schizophrenia. Proc Natl Acad Sci U S A. 2005 Jun 14;102(24):8627-32. Epub 2005 Jun 6. Abstract

Cannon TD, Hennah W, van Erp TG, Thompson PM, Lonnqvist J, Huttunen M, Gasperoni T, Tuulio-Henriksson A, Pirkola T, Toga AW, Kaprio J, Mazziotta J, Peltonen L. Association of DISC1/TRAX haplotypes with schizophrenia, reduced prefrontal gray matter, and impaired short- and long-term memory. Arch Gen Psychiatry, 2005; 62(11):1205-1213. Abstract

Hennah W, Tuulio-Henriksson A, Paunio T, Ekelund J, Varilo T, Partonen T, Cannon TD, Lonnquist J, Peltonen L. A haplotype within the DISC1 gene is associated with visual memory functions in families with high density of schizophrenia. Mol Psychiatry 2005; 10(12):1097-1103. Abstract

Lencz T, Bilder RM, Turkel E, Goldman RS, Robinson D, Kane JM, Lieberman JA. Impairments in perceptual competency and maintenance on a visual delayed match-to-sample test in first episode schizophrenia. Arch Gen Psychiatry 2003; 60(3):238-243. Abstract

View all comments by Anil Malhotra
View all comments by Katherine E. Burdick

Related News: Nature Makes a DISC1-Deficient, Forgetful Mouse

Comment by:  J David Jentsch
Submitted 7 March 2006
Posted 7 March 2006
  I recommend the Primary Papers

In their recent paper, Koike et al. provide new evidence in support of a genetic determinant of working memory function in the vicinity of the mouse DISC1 gene. They report their discovery of a naturally occurring DISC1 deletion variant in the 129S6/SvEv mouse strain that leads to reduced protein expression and that provides a potentially very important new tool for analyzing the cellular and behavioral phenotypes associated with DISC1 insufficiency. Given the strong evidence of a relationship between a cytogenetic abnormality that leads to DISC1 truncation in humans and major mental illness (Millar et al., 2000), this murine model stands to greatly serve our understanding of the molecular and cellular determinants of poor cognition in schizophrenia and bipolar disorder.

The authors are parsimonious in reminding us of the substantial limitations of models such as this. Specifically, the current approach does not allow for a clear statement that the DISC1 gene itself modulates the traits of interest. The DISC1 deletion variant may simply be in linkage disequilibrium with the actual phenotype-determining gene, and/or variation in DISC1 may influence cognition in a manner that is modified by a nearby genetic region. For example, Cannon et al. recently showed that a 4-SNP haplotype spanning DISC1 and an adjacent gene, translin-associated factor X (TRAX) is more predictive of anatomical and cognitive indices of reduced prefrontal cortical and hippocampal function than are any known haplotypes spanning DISC1 only. Clearly, additional consideration of the genetic environment in which DISC1 lies is necessary, and discovery of flanking regions that contain modifiers of the actions of DISC1, and vice versa, would be extremely interesting.

The greatest impact of the paper by Koike et al. is hinged on the fact that mice carrying one or two copies of the deletion variant exhibit poor choice accuracy in a delayed non-match to position task. Specifically, mutant DISC1 mice made fewer correct choices than did wild-type littermate C57 mice. Because a procedure such as this is necessarily psychologically complex, performance failure is hardly prima facie evidence for impairments of spatial working memory, or for prefrontal cortical dysfunction, in general. Nevertheless, the data are remarkable in establishing a phenotypic bridge between species and in laying the foundation for more sophisticated behavioral studies that will narrow in on the psychological constructs and neural systems affected by variation in this genetic region. Through facilitating a greater understanding of the cognitive phenotypes associated with DISC1 variation, the model should open doors to understanding key phenotypic aspects of schizophrenia and bipolar disorder.


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 U S A. 2006 Feb 16; [Epub ahead of print] Abstract

Millar JK, Wilson-Annan JC, Anderson S, Christie S, Taylor MS, Semple CA, Devon RS, Clair DM, Muir WJ, Blackwood DH, Porteous DJ. Disruption of two novel genes by a translocation co-segregating with schizophrenia. Hum Mol Genet. 2000 May 22;9(9):1415-23. Abstract

Cannon TD, Hennah W, van Erp TG, Thompson PM, Lonnqvist J, Huttunen M, Gasperoni T, Tuulio-Henriksson A, Pirkola T, Toga AW, Kaprio J, Mazziotta J, Peltonen L. Association of DISC1/TRAX haplotypes with schizophrenia, reduced prefrontal gray matter, and impaired short- and long-term memory. Arch Gen Psychiatry. 2005 Nov;62(11):1205-13. Abstract

View all comments by J David Jentsch

Related News: Nature Makes a DISC1-Deficient, Forgetful Mouse

Comment by:  Kirsty Millar
Submitted 13 March 2006
Posted 13 March 2006
  I recommend the Primary Papers

Disrupted In Schizophrenia 1 was first identified as a genetic susceptibility factor in schizophrenia because it is disrupted by a translocation between chromosomes 1 and 11 in a large Scottish family with a high loading of schizophrenia and related mental illness. Since then, numerous genetic studies have implicated DISC1 as a risk factor in psychiatric illness in several populations. Given the limitations on studies using brain tissue from patients, an obvious next step was to engineer knockout mice, but these have been slow in coming. As a first step toward this, Kioke and colleagues now report an unexpected naturally occurring genetic variant in the 129/SvEv mouse strain.

Kioke et al. report that the 129/SvEv mouse strain carries a 25 bp deletion in DISC1 exon 6, and that this results in a shift of open reading frame and introduction of a premature stop codon. Several embryonal stem cell lines have been isolated for the 129 strain, favoring it for gene targeting studies. However, this strain has a number of well-established behavioral characteristics ( Therefore, to assign any phenotype specifically to the DISC1 deletion variant, the 129 DISC1 variant had to be transferred to a C57BL/6J background, with its own, rather different but equally characteristic behavior ( There were no detectable gross morphological alterations in the prefrontal cortex, cortex, and hippocampus on transferring the 129 DISC1 locus onto the C57BL/6J background. However, the mutation did result in working memory deficits, consistent with several reports linking DISC1 to cognition.

It is difficult to know what phenotype to expect from a mouse model for schizophrenia, but in humans it is widely believed that mutations confer only a susceptibility to developing illness. Many susceptible individuals function apparently normally, although subtle neurological endophenotypes are detectable. In individuals who do go on to develop schizophrenia, cognitive deficits are a major characteristic. These mild cognitive deficits in mice with loss of DISC1 function are therefore close to what we might predict.

The molecular mechanism by which DISC1 confers susceptibility to psychiatric illness is the subject of some debate. Sawa and colleagues have suggested that a mutant truncated protein resulting from the t(1;11) is responsible for the psychiatric disorders in the Scottish family. Millar and colleagues, however, report that there is no evidence for such a hypothetical protein in t(1;11) cell lines, but rather that the levels of DISC1 transcript and protein are reduced, consistent with a haploinsufficiency model. Identification of the deletion in mice may shed further light on this debate, since while the mutation does not affect DISC1 transcript levels, no mutant truncated protein is detectable, even though such a protein might theoretically be produced as a result of the premature stop codon. Moreover, both homozygotes and heterozygotes have cognitive impairment, demonstrating that DISC1 haploinsufficiency is sufficient to affect central nervous system function.

In this initial study, Kioke and colleagues have left many questions unanswered. In particular, the behavioral studies are limited to one working memory task and one test of locomotion. Ideally, a whole battery of behavioral and cognitive tests should be performed. Since 129/SvEv mice reportedly have impaired hippocampal function, high levels of anxiety-like behavior and altered NMDA receptor-related activity, it will be interesting to discover which, if any, of these phenotypes also co-segregate with the 129 DISC1 variant. It is also interesting to note that the 129 strain is effectively a null for full-length DISC1, but with no gross alteration in brain morphology. This has to be reconciled with the observed effect of transient RNAi mediated down-regulated expression in utero (Kamiya et al., 2005) and the possible, but still anecdotal observation of embryonic lethality in experimental DISC1 knockouts.

View all comments by Kirsty Millar

Related News: DISC1 Delivers—Genetic, Molecular Studies Link Protein to Axonal Transport

Comment by:  Akira Sawa, SRF Advisor
Submitted 12 January 2007
Posted 12 January 2007

Although DISC1 is multifunctional, its role for neurite outgrowth has been substantially characterized for the past couple of years (Ozeki et al., 2003; Miyoshi et al., 2003; Kamiya et al., 2006). These studies indicated that DISC1 is involved in neurite outgrowth by more than one mechanism, such as interactions with NUDEL/NDEL1 and FEZ1.

These two papers from Kaibuchi’s lab provide further understanding of how DISC1 is involved in neuronal outgrowth. Kaibuchi’s group identified kinesin heavy chain of kinesin-1 as a novel interactor of DISC1. In their papers, a novel role for DISC1, to link kinesin-1 (microtubule-dependent and plus-end directed motor) to several cellular molecules, including NUDEL, LIS1, 14-3-3, and Grb2, is reported. DISC1 and kinesin-1 are, therefore, responsible to sort Grb2 to the distal part of axons where Grb2 functions as an adaptor and plays a role in NT-3-induced phosphorylation of ERK1/2. This mechanism well explains our previous work, led by Ryota Hashimoto, reporting that knockdown of DISC1 expression results in decreased levels of phosphorylation of ERK1/2 and Akt in primary cortical neurons (Hashimoto et al., 2006).

The interaction of DISC1 and kinesin-1 may also be interesting from the perspective of psychiatric genetics. First, the mechanism proposed in one of the papers (Taya et al., 2007) supports the notion that the C-terminal truncated DISC1 fragment—that occurs due to the balanced translocation in an extended Scottish family—functions as a dominant-negative. Second, the domain of DISC1 responsible for kinesin-1 is overlapped with the haplotype block region(s) that are positive in more than one association study of DISC1 and major mental illnesses.

View all comments by Akira Sawa

Related News: DISC1 Delivers—Genetic, Molecular Studies Link Protein to Axonal Transport

Comment by:  Luiz Miguel Camargo (Disclosure)
Submitted 13 January 2007
Posted 13 January 2007

Two recent back-to-back papers, published this month in Journal of Neuroscience, highlight the value of protein-protein interactions in determining the biological role of a key schizophrenia risk factor, DISC1, in processes that are important for the proper development of neurons.

Key questions need to be addressed once having established a set of interactors for a given protein. First, where do these proteins interact on the target molecule? Second, do these interactions take place at the same time (i.e., do they form a complex)? Third, in what context do these interactions occur (temporal, tissue/cell compartment, signaling), and, fourth, are the biological processes of the interacting molecules affected/regulated by the protein of interest? The Kaibuchi lab, as exemplified in the works by Taya et al. and Shinoda et al., elegantly address some of these questions in the context of DISC1 interactions with Grb2, Nudel (NDEL1), 14-3-3ε, and kinesin-1. The key findings of these papers are as follows:

1. Identification of the interaction sites, or more importantly, which part of DISC1 is involved in particular processes, for example, that axon elongation is dependent on the N-terminal, but not the C-terminal portion of DISC1. This suggests that the DISC1 role in axon elongation is mediated by interactions with the N-terminal portion of DISC1 that could be competed for by the truncated protein in a dominant negative fashion (Camargo et al., 2007).

2. Although a protein may have many interacting partners, such as DISC1, these interactions may not occur at the same time. For example, DISC1 is able to form a ternary complex with kinesin-1 and NDEL1 or with kinesin-1 and Grb2. However, a ternary complex of DISC1-Grb2-NDEL1 is not possible as Grb2 and NDEL1 may be competing for the same interaction site on DISC1.

3. Protein interactions may occur in certain cellular compartments, in the case of DISC1, the cell body and the distal part of axons.

4. Neurotrophin-induced axon elongation requires DISC1.

These papers confirm some of the hypotheses raised by the interactions that we have recently derived for DISC1 and some of its interacting partners (see Camargo et al., 2007). From the DISC1 interactome, we concluded that DISC1 may affect key intracellular transport mechanisms, such as those regulated by kinesins, and that DISC1 may be downstream of neurotrophin receptors, via its interaction with SH3BP5, an adaptor protein, which we found to interact with SOS1, a guanine exchange factor that binds Grb2 and responds to signaling of neurotrophin receptors. These observations have been validated by Taya et al. and Shinoda et al. and demonstrate the value of the DISC1 interactome in understanding the role of DISC1, and as a valuable resource to the wider community.

The molecular function of DISC1, as defined by its structure, still remains elusive, requiring a more dedicated effort on this front. The good news is that, via its protein-protein interactions, significant progress on the role of DISC1 in key biological processes has been achieved, as illustrated by the work of different labs (Brandon et. al., 2004; Millar et al., 2005; Kamiya et al., 2005; and now by Shinoda et al. and Taya et al.).

View all comments by Luiz Miguel Camargo

Related News: Working Memory—Adrenoreceptors and DISC1 in the Same cAMP?

Comment by:  Joseph Friedman
Submitted 11 May 2007
Posted 11 May 2007

Cognitive symptoms have emerged as an independent feature of schizophrenia that needs to be targeted for treatment independent of more well-known symptoms such as hallucinations and delusions. Indeed, the level of impairment in cognitive abilities is one of the strongest predictors of impaired adaptive life skills in patients with schizophrenia. The prefrontal cortex, critical for cognitive abilities such as working memory and executive functions, is well established to be dysfunctional in patients with schizophrenia. Although the significance of dopamine-related changes to the prefrontal cortex in schizophrenia has been extensively studied, noradrenergic changes are also important, but often overlooked. Moreover, second-generation antipsychotics, which partially address the reduced prefrontal dopamine activity in patients with schizophrenia, have only modest effects on the cognitive impairments associated with schizophrenia.

Alpha-2 noradrenergic agonists, such as the antihypertensive drug guanfacine, increase noradrenergic activity in the prefrontal cortex. Evidence demonstrating cognitive-enhancing effects of guanfacine on cognitive abilities related to the prefrontal cortex in both animals and healthy human subjects suggests a potential role for guanfacine in treating some of the cognitive impairments of schizophrenia. Although limited, there is some evidence in support of cognitive enhancing effects of guanfacine in patients with schizophrenia (Friedman et al., 2001). Our current clinical trial seeks to determine the reproducibility of these preliminary results and assess the potential effects of guanfacine on the adaptive life skills of patients with schizophrenia. This study is being conducted in the New York State Mental Health System, specifically at Pilgrim Psychiatric Center (Mount Sinai Hospital is the sponsor) and at the Bronx Veterans Administration Medical Center (the sponsor is the VISN3 MIRECC). We expect results by end of year 2008.

Should guanfacine be effective, my plan would be to try to obtain federal funding for a larger multi-site study of guanfacine in combination with either a social skills or cognitive skills rehabilitation program. However, even if proven effective, it is important to keep in mind that any potential guanfacine effects will be limited to cognitive abilities associated with the prefrontal cortex. As data from animal models and healthy human subjects indicate, guanfacine will most likely be ineffective in addressing important cognitive symptoms related to temporal lobe changes in schizophrenia.

View all comments by Joseph Friedman

Related News: Modeling Schizophrenia Phenotypes—DISC1 Transgenic Mouse Debuts

Comment by:  David J. Porteous, SRF AdvisorKirsty Millar
Submitted 2 August 2007
Posted 2 August 2007

Several genetic studies point to involvement of DISC1 in major psychiatric illness, including schizophrenia and bipolar disorder, but to date the only causal variant that has been definitively identified is the translocation between human chromosomes 1 and 11 that co-segregates with major mental illness in a large Scottish family and which directly disrupts the DISC1 gene (Millar at al., 2000). It has been speculated that a truncated form of DISC1 may be expressed from the translocated allele and, if so, that this could exert a dominant-negative effect, but there is no such evidence from studies of the translocation cases. Rather, the evidence from studies of lymphoblastoid cell lines carrying the translocation suggests that haploinsufficiency is the most likely disease mechanism in this family (Millar et al., 2005). The unresolvable caveat to this, of course, is that it has not been possible to determine whether this is true also for the brain. Moreover, it is far from certain that any productive product from the translocation chromosome would be a perfectly truncated protein encoded by all the remaining exons, as opposed to an exon-skip isoform, with or without a hybrid protein component borrowing sequence information from chromosome 11. What does seem likely from other human studies is that additional genetic mechanisms, including missense mutations, altered expression, and possibly also copy number variation, play a role in the generality of DISC1 as a risk factor.

The evidence in support of DISC1 as an important biological determinant across a spectrum of major mental illness has now received a further boost from the study in PNAS by Hikida et al. The Sawa lab describes a transgenic approach where a truncated human DISC1 protein is expressed from a CAMKII promoter. The truncation was designed to mimic the hypothetical truncation arising from the Scottish translocation. This forebrain-specific promoter confers preferential expression of the transgene at neonatal stages, as distinct from the expression of the endogenous protein, which is abundant from embryonic development into adulthood. This model therefore permits investigation of the effect of the truncated protein in the forebrain within a specific developmental window, against a background of endogenous mouse DISC1 expression. Since there is no evidence for production of a truncated protein from the translocated allele, the relevance of this model to psychiatric illness remains unclear. However, on the positive side and from a functional perspective, dominant-negative effects as a consequence of expressing the truncated protein have already been demonstrated in cultured cells, altering the subcellular distribution of DISC1 and interaction with DISC1 partner proteins. Moreover, expression of the truncated form of DISC1 mimics downregulation of DISC1 in vivo, inhibiting migration of neurons in the developing mouse cortex (Kamiya et al., 2005). Thus, this model has the genuine potential to enhance our understanding of the biology of DISC1.

This is, in fact, the third study describing mice expressing modified DISC1 alleles. In the first study, Gogos and colleagues (Kioke et al., 2006) studied the effects of a modified DISC1 allele carrying a spontaneous 25 bp deletion in exon 6 that is present in all 129 mouse strains (Koike et al., 2007; see SRF related news story). This allele additionally has an artificial stop codon in exon 8 and a downstream polyadenylation signal. After back-crossing this mutagenised version of the 129 allele onto a C57Bl6 background, they reported a deficit in an assay of working memory in both heterozygous and homozygous mutants, but other standard behavioral tests were unaltered or unreported, and there were no anatomical, electrophysiological, or pharmacological studies included. In the second study, one led by the Roder laboratory, Toronto, we described two mouse strains with missense mutations in exon 2, Q31L and L100P (Clapcote et al., 2007). Reductions in brain volume, deficits in a range of standard behavioral tests, and responses to pharmacological treatments were reported, which can be summarized as consistent with the 100P mutants displaying schizophrenia-like phenotypes and the 31L mutants, mood disorder-like phenotypes. There is a frustrating dearth of consistent biomarkers for schizophrenia, but one of the best replicated findings is by brain imaging of enlarged ventricles in schizophrenia (also, but less markedly, in bipolar disorder). Adding to the observations of Clapcote et al., arguably the most striking claim by Hikida et al. is for altered ventricular brain volume and reduced brain laterality following neonatal transgenic overexpression of truncated DISC1. Additionally, behavioral tests were reported that overlap in part with those reported earlier by Clapcote et al. That three studies all describe behavioral abnormalities consistent with modeling components of schizophrenia is reassuring. That there are clear differences, too, between the phenotypes should come as no surprise either, given the important differences in terms of genetic lesion and developmental expression. Other mouse models are in the pipeline and they, too, will be welcomed. Indeed, this is very much what is needed for the field to move forward. But we should do so with some caution, paying careful attention to the specific nature of the models, what they can and cannot tell us about DISC1 biology, and what they may or may not tell us about the human condition. Although none of these models relates directly to a known causal variant, it appears that the mouse models concur with the human genetic studies in suggesting that there are likely to be several routes by which DISC1 can perturb brain function leading to characteristics of human mental illness. What we need now is for the human genetic studies to catch up with the mouse so that defined pathognomic variants can be modeled.

View all comments by David J. Porteous
View all comments by Kirsty Millar

Related News: Modeling Schizophrenia Phenotypes—DISC1 Transgenic Mouse Debuts

Comment by:  John Roder
Submitted 2 August 2007
Posted 2 August 2007

A new mouse model from the Sawa lab strengthens the evidence for the candidate gene DISC1 playing a role in psychosis and mood disorders. This important paper is the first to address one potential disease mechanism, that of a dominant-negative effect. Expression of the C-terminal deletion of human DISC1—which represented the original rearrangement found by the Porteous group in the Scottish families with schizophrenia and depression—in transgenic mice driven by the α CaMKII promoter, first described by Mark Mayford when a postdoctoral fellow in the Kandel lab, leads to mice showing behaviors consistent with schizophrenia and depression, with enlarged lateral ventricles. Since the Sawa group expressed the human C-terminal truncation in mouse with no change in mouse DISC1 levels, they feel this supports a dominant-negative mechanism. More direct experiments are required. For example, create a null mutant mouse for DISC1 and express the full-length and truncated human DISC1 under the influence of their own promoter in transgenic mice using human BACs. Full-length human DISC1 would, hopefully, rescue the null. If so, then a mixture of full-length and truncated DISC1 proteins could be tried. No rescue by the mixture of full-length and truncated proteins would suggest a dominant-negative mechanism.

The Porteous group has shown no detectable DISC1 protein in lymphoblasts from the patients, and put forward the following implicit model. The C-terminal truncation of DISC1 makes the protein unstable and sensitive to degradation, a plausible alternative notion. In my opinion both are likely in different schizophrenia patients with perturbations in DISC1, most of which are alterations other than the C-terminal truncation. Some have SNPs that lead to as yet uncharacterized disease. It has been shown by the Sawa lab that mice with a partial RNAi knockdown of DISC1 show perturbations in brain development, and if aged to 8-12 weeks these mice might have shown behavioral and neuropathological hallmarks of schizophrenia and depression. There is currently no null mutation in the mouse that would address this issue, although DISC1 is one of the genes being targeted in the NIH knockout mouse project. Fortunately, there are now several mouse models—the more the better. The Gogos lab has a 25bp deletion in exon 6 that removes some, but not all isoforms. The Roder lab used a reverse genetic screen of an ENU archive to generate two missense mutants in non-conserved amino acids. The phenotypes of all these lines are nicely summarized in the Sawa paper. This work represents a step forward in our understanding of the DISC1 gene.

View all comments by John Roder

Related News: DISC1: A Maestro of Adult Hippocampal Neurogenesis?

Comment by:  Barbara K. Lipska
Submitted 9 September 2007
Posted 9 September 2007

Several recent studies on disruptions of the DISC1 gene in mice illustrate the great potential of genetic approaches to studying functions of putative schizophrenia susceptibility genes but also signal the complexity of the problem. An initial rationale for studying the effects of mutations in DISC1 came from the discovery of the chromosomal translocation, resulting in a breakpoint in the DISC1 gene that co-segregated with major mental illness in a Scottish family (reviewed by Porteous et al., 2006). These clinical findings were followed by a number of association studies, which reported that numerous SNPs across the gene were associated with schizophrenia and mood disorders and a variety of intermediate phenotypes, suggesting that other problems in the DISC1 gene may exist in other subjects/populations.

Recent animal models designed to mimic partial loss of DISC1 function suggested that DISC1 is necessary to support development of the cerebral cortex as its loss resulted in impaired neurite outgrowth and the spectrum of behavioral abnormalities characteristic of major mental disorders ( Kamiya et al., 2005; Koike et al., 2006; Clapcote et al., 2007; Hikida et al. 2007). Unexpectedly, however, the paper by Duan et al., 2007, is showing that DISC1 may also function as a brake and master regulator of neuronal development, and that its partial loss could lead to the opposite effects than previously described, i.e., dendritic overgrowth and accelerated synapse formation and faster maturation of newly generated neurons. In contrast to previous studies, they have used the DISC1 knockdown model achieved by RNA interference in a subpopulation of single cells of the dentate gyrus. Other emerging studies continue to reveal the highly complex nature of the DISC1 gene with multiple isoforms exhibiting different functions, perhaps depending on localization, timing, and interactions with a multitude of other genes’ products, some of which confer susceptibility to mental illness independent of DISC1. Similar molecular complexity has also emerged in other susceptibility genes for schizophrenia: GRM3 (Sartorius et al., 2006), NRG1 (Tan et al., 2007), and COMT (Tunbridge et al., 2007). With the growing knowledge about transcript complexity, it becomes increasingly clear that subtle disturbances of isoform(s) of susceptibility gene products and disruptions of intricate interactions between the susceptibility genes may account for the etiology of neuropsychiatric disorders. Research in animals will have a critical role in disentangling this web of interwoven genetic pathways.

View all comments by Barbara K. Lipska

Related News: DISC1: A Maestro of Adult Hippocampal Neurogenesis?

Comment by:  Akira Sawa, SRF Advisor
Submitted 13 September 2007
Posted 13 September 2007

I am very glad that our colleagues at Johns Hopkins University have published a very intriguing paper in Cell, showing a novel role for DISC1 in adult hippocampus. This is very consistent with previous publications (Miyoshi et al., 2003; Kamiya et al., 2005; and others; reviewed by Ishizuka et al., 2006), and adds a new insight into a key role for DISC1 during neurodevelopment. In short, DISC1 is a very important regulator in various phases of neurodevelopment, which is reinforced in this study. Specifically, DISC1 is crucial for regulating neuronal migration and dendritic development—for acceleration in the developing cerebral cortex, and for braking in the adult hippocampus.

There is precedence for signaling molecules playing the same role in different contexts, with the resulting molecular activity going in different directions. For example, FOXO3 (a member of the Forkhead transcription factor family) plays a role in cell survival/death in a bidirectional manner (Brunet et al., 2004). FOXO3 endows cells with resistance to oxidative stress in some contexts, and induces apoptosis in other contexts. SIRT1 (known as a key modulator of organismal lifespan) deacetylates FOXO3 and tips FOXO3-dependent responses away from apoptosis and toward stress resistance. In analogy to FOXO3, context-dependent post-translational modifications, such as phosphorylation, may be an underlying mechanism for DISC1 to function in a bidirectional manner. Indeed, a collaborative team at Johns Hopkins, including Pletnikov's lab, Song's lab, and ours, has started exploring, in both cell and animal models, the molecular switch that makes DISC1's effects bidirectional.


Brunet A, Sweeney LB, Sturgill JF, Chua KF, Greer PL, Lin Y, Tran H, Ross SE, Mostoslavsky R, Cohen HY, Hu LS, Cheng HL, Jedrychowski MP, Gygi SP, Sinclair DA, Alt FW, Greenberg ME. Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase. Science. 2004 Mar 26;303(5666):2011-5. Abstract

View all comments by Akira Sawa

Related News: DISC1: A Maestro of Adult Hippocampal Neurogenesis?

Comment by:  Sharon Eastwood
Submitted 14 September 2007
Posted 14 September 2007

Recent findings, including the interactome study by Camargo et al., 2007, and this beautiful study by Duan and colleagues, implicate DISC1 (a leading candidate schizophrenia susceptibility gene) in synaptic function, consistent with prevailing ideas of the disorder as one of the synapse and connectivity (see Stephan et al., 2006). As we learn more about DISC1 and its protein partners, evidence demonstrating the importance of microtubules in the regulation of several neuronal processes (see Eastwood et al., 2006, for review) suggests that DISC1’s interactions with microtubule associated proteins (MAPs) may underpin its pathogenic influence.

DISC1 has been shown to bind to several MAPs (e.g., MAP1A, MIPT3) and other proteins important in regulating microtubule function (see Kamiya et al., 2005; Porteous et al., 2006). As a key component of the cell cytoskeleton, microtubules are involved in many cellular processes including mitosis, motility, vesicle transport, and morphology, and their dynamics are regulated by MAPs, which modulate microtubule polymerization, stability, and arrangement. Decreased microtubule stability in mutant mice for one MAP, stable tubule only polypeptide (STOP; MAP6), results in behavioral changes relevant to schizophrenia and altered synaptic protein expression (Andrieux et al., 2002; Eastwood et al., 2006), indicating the importance of microtubules in synaptic function and suggesting that they may be a molecular mechanism contributing to the pathogenesis of schizophrenia. Likewise, DISC1 mutant mice exhibit behavioral alterations characteristic of psychiatric disorders (e.g., Clapcote et al., 2007), and altered microtubule dynamics are thought to underlie perturbations in cerebral cortex development and neurite outgrowth caused by decreased DISC1 expression or that of a schizophrenia-associated DISC1 mutation (Kamiya et al., 2005).

Our interpretation of the possible functions of DISC1 has been complicated by the unexpected findings of Duan and colleagues that DISC1 downregulation during adult hippocampal neurogenesis leads to overextended neuronal migration and accelerated dendritic outgrowth and synaptic formation. In terms of neuronal positioning, they suggest that their results indicate that DISC1 may relay positional signals to the intracellular machinery, rather than directly mediate migration. In this way, decreased DISC1 expression may result in the mispositioning of newly formed neurons rather than a simple decrease or increase in their migratory distance. Of note, MAP1B, a neuron-specific MAP important in regulating microtubule stability and the crosstalk between microtubules and actin, is required for neurons to correctly respond to netrin 1 signaling during neuronal migration and axonal guidance (Del Rio et al., 2004), and DISC1 may function similarly during migration. Reconciling differences between the effect of decreased DISC1 expression upon neurite outgrowth during neurodevelopment and adult neurogenesis is more difficult, but could be due to differences in the complement of MAPs expressed by different neuronal populations at different times. Regardless, the results of Duan and colleagues have provided additional evidence implicating DISC1 in neuronal functions thought to go awry in schizophrenia. Further characterization of DISC1’s interactions with microtubules and MAPs may lead to a better understanding of the role of DISC1 in the pathogenesis of psychiatric disorders.


Andrieux A, Salin PA, Vernet M, Kujala P, Baratier J, Gory Faure S, Bosc C, Pointu H, Proietto D, Schweitzer A, Denarier E, Klumperman J, Job D (2002). The suppression of brain cold-stable microtubules in mice induces synaptic deficits associated with neuroleptic-sensitive behavioural disorders. Genes Dev. 16: 2350-2364. Abstract

Camargo LM, Collura V, Rain JC, Mizuguchi K, Hermjakob H, Kerrien S, Bonnert TP, Whiting PJ, Brandon NJ (2007). Disrupted in Schizophrenia 1 Interactome: evidence for the close connectivity of risk genes and a potential synaptic basis for schizophrenia. Mol. Psychiatry 12: 74-86. Abstract

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 (2007). Behavioral phenotypes of Disc1 missense mutations in mice. Neuron 54: 387-402. Abstract

Del Rio, J.A., Gonzalez-Billault, C., Urena, J.M., Jimenez, E.M., Barallobre, M.J., Pascual, M., Pujadas, L., Simo, S., La Torre, A., Wandosell, F., Avila, J. and Soriano, E. (2004). MAP1B is required for netrin 1 signaling in neuronal migration and axonal guidance. Cur. Biol. 14: 840-850. Abstract

Eastwood SL, Lyon L, George L, Andrieux A, Job D, Harrison PJ (2006). Altered expression of synaptic protein mRNAs in STOP (MAP6) mutant mice. J. Psychopharm. 21: 635-644. 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

Porteous DJ, Thomson P, Brandon NJ, Millar JK (2006). The genetics and biology of DISC1-an emerging role in psychosis and cognition. Biol. Psychiatry 60: 123-131. Abstract

Stephan KE, Baldeweg T, Friston KJ (2006). Synaptic plasticity and disconnection in schizophrenia. Biol. Psychiatry 59: 929-939. Abstract

View all comments by Sharon Eastwood

Related News: Inducing Schizophrenic Behavior? Researchers Roll Out New DISC1 Mouse

Comment by:  John RoderSteven Clapcote
Submitted 17 September 2007
Posted 17 September 2007

This is a useful model from Pletnikov, Ross, and colleagues, but like all models, it has some limitations. Since DISC1 is known to have a strong role in development and physiology, the development of inducible mutants is necessary to separate the two.

In the TeT-off system used in the paper, mice must be treated with doxycycline for their entire lives to keep the expression of this gene off. Doxycycline must be used at high levels and may have side effects when used this long. The TeT-on system is better because doxycycline is only used transiently for 1 week for maximum induction then washed away. The TeT-on system is also available for the same promoter used in the paper, that of the CaMKII gene.

The phenotype of reduced neurite length was obtained from in vitro neuron cultures, which are prone to artifacts. There are ways of labeling these neurons in vivo for measuring neurite length and spines. The brain phenotype was obtained by MRI. There are ways, such as adding manganese, of enhancing active pathways. This has been done in the bird brain to map song pathways.

The behavioral phenotype was similar to the recent paper from the Sawa group (Hikida et al., 2007) in that it also analyzed a transgenic mouse expressing the same C-terminal truncation of the human DISC1 gene, using the same CaMKII promoter. An important difference in the findings was a reduction of murine DISC1 (50 percent at protein level) in the Pletnikov et al. mice but none in the Sawa group mice. This issue is important because of a recent paper in Cell by the Song group (Duan et al., 2007). In that paper, RNAi was used to reduce wild-type native murine DISC1. Individual neurons with targeted DISC1 knockdown showed accelerated neurite development, greater synapse formation and enhanced excitability. Hippocampal granule cells showed accelerated morphological integration resulting in mispositioning. Unfortunately, in the Song paper they analyzed only cells with complete or no knockdown of DISC1. Partial knockdown vectors were made that achieved 75 percent reduction at the protein level but were not analyzed. Only then would it be possible to compare these morphological data with those from Pletnikov et al., which was a 50 percent reduction. Another difference was that the Song group found that DISC1 needed to interact with Nudel. Pletnikov et al. found normal levels of Nudel in the mice but lower LIS1, which could explain the brain development phenotype.

View all comments by John Roder
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Related News: DISC1 Is Critical for Axon Terminals in Adult Hippocampus

Comment by:  Jill MorrisKate Meyer
Submitted 3 October 2008
Posted 6 October 2008
  I recommend the Primary Papers

The elegant research by Faulkner and colleagues, along with their previous work (Duan et al., 2007), clearly demonstrates a role for DISC1 in regulating the timing of neuronal development in the adult brain. The loss of Disc1 in adult-born dentate granule cells resulted in aberrant axonal targeting and accelerated mossy fiber maturation. Although it is hypothesized that the hippocampus is involved in the pathophysiology of schizophrenia, the cellular and molecular underpinnings of hippocampal dysfunction are unknown. However, it is becoming apparent that Disc1 is a regulator of granule cell integration and maturation in the adult hippocampus. The function of adult-born granule cells and the contribution they make to hippocampal function is, of course, yet to be fully elucidated. In the context of schizophrenia, though, it may be that abnormal incorporation of newborn granule cells into the hippocampal network—perhaps caused by mutations in key genes such as Disc1—is a post-developmental trigger which leads to the onset of disease symptoms.

The finding that Disc1 regulates mossy fiber targeting and synapse formation is also intriguing on a more general level. There is much research suggesting that schizophrenia is a disease of the synapse, likely involving several neurotransmitter systems. A role for Disc1 in axon outgrowth and synapse formation would certainly be a means through which Disc1 disruption could affect the hippocampal trisynaptic circuit. Next, we as researchers will have to determine the molecular mechanisms by which Disc1 is regulating neuronal development and axonal targeting. Based on the work in the developing and adult brain, Disc1 has multiple cellular roles involving a long list of interactors. The challenge is determining which Disc1 functions and pathways are relevant to the schizophrenia phenotype.


Duan X, Chang JH, Ge S, Faulkner RL, Kim JY, Kitabatake Y, Liu XB, Yang CH, Jordan JD, Ma DK, Liu CY, Ganesan S, Cheng HJ, Ming GL, Lu B, Song H. Disrupted-In-Schizophrenia 1 regulates integration of newly generated neurons in the adult brain. Cell. 2007 Sep 21;130(6):1146-58. Abstract

View all comments by Jill Morris
View all comments by Kate Meyer

Related News: DISC1: A Matter of Life or Death for Neural Progenitors

Comment by:  Khaled Rahman
Submitted 26 March 2009
Posted 26 March 2009

Mao and colleagues present an impressive body of work implicating GSK3β/β-catenin signaling in the function of Disc1. However, several key experimental controls are missing that detract from the impact of their study, and it is unclear whether this function of Disc1 among its many others is the critical link between the t(1;11) translocation and psychopathology in the Scottish family.

The results of Mao et al. suggest that acute knockdown of Disc1 in embryonic brain causes premature exit from the proliferative cell cycle and premature differentiation into neurons. In fact, they observe fewer GFP+ cells in the VZ/SVZ and greater GFP+ cells within the cortical plate. This is in contrast to the study by Kamiya et al. (2005), in which they find that knocking down Disc1 caused greater retention of cells in the VZ/SVZ and fewer in the cortical plate, suggesting retarded migration. Although the timing of electroporation (E13 vs. E14.5) and examination (E15 vs. P2) differed between the two studies, these results are not easily reconciled.

The authors also suggest that they can rescue the deficits in proliferation by overexpressing human wild-type DISC1, stabilizing β-catenin expression, or inhibiting GSK3β activity, and thus conclude that Disc1 is acting through this pathway. This conclusion, however, rests on an error in logic. If increasing X causes an increase in Y, and decreasing Z causes a decrease in Y, this does not mean that X and Z are operating via the same mechanism. In fact, overexpressing WT-DISC1, stabilizing β-catenin, or inhibiting GSK3β activity all increase proliferation in control cells. Thus, the fact that these manipulations also work in progenitors with Disc1 silenced only tells us that these effects are independent or downstream of Disc1. What are needed are studies that show a differential sensitivity of Disc1-silenced cells to manipulations of β-catenin or GSK3β. In other words, is there a shift in the dose response curves? This is what is to be expected given that Mao et al. show changes in β-catenin levels and changes in the phosphorylation of GSK3β substrates in Disc1 silenced cells.

Furthermore, it is surprising that a restricted silencing of Disc1 in the adult dentate gyrus produces changes in affective behaviors, when total ablation of dentate neurogenesis in the adult produces little effects on depression-related behaviors (Santarelli et al., 2003; Airen et al., 2007). The fact that inhibiting GSK3β increases proliferation in both control and Disc1 knockdown animals to a similar degree suggests that the “rescue” of any behavioral deficits is independent of the drug’s effects on proliferation. Correlating measures of proliferation with behavioral performance would help address this issue.

How this study will lead to new or improved therapeutic interventions is also an open question. Lithium is well known for its mood-stabilizing properties, and this study may point to better, more efficient ways to address these symptoms. However, it is also known that lithium does little for, if not worsens, cognitive symptoms in patients (Pachet and Wisniewski, 2003), and it is this symptom domain that is in dire need of drug development.

It is also important to keep in mind that acute silencing of Disc1 in a restricted set of cells will not necessarily recapitulate the pathogenetic process of a disease-associated mutation. It remains to be seen if similar results are obtained in animal models of the Disc1 mutation (Clapcote et al., 2007; Hikida et al., 2007; Li et al., 2007).


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 1;7(12):1167-78. Abstract

Santarelli, L. et al. Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science 301, 805–809 (2003). Abstract

Airan, R.D. et al. High-speed imaging reveals neurophysiological links to behavior in an animal model of depression. Science 317, 819-23 (2007). Abstract

Pachet AK, Wisniewski AM. The effects of lithium on cognition: an updated review. Psychopharmacology (Berl). 2003 Nov;170(3):225-34. Review. Abstract

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

Hikida T, Jaaro-Peled H, Seshadri S, Oishi K, Hookway C, et al. (2007) Dominant-negative DISC1 transgenic mice display schizophrenia-associated phenotypes detected by measures translatable to humans. Proc Natl Acad Sci U S A 104: 14501–14506. Abstract

Li W, Zhou Y, Jentsch JD, Brown RA, Tian X, et al. (2007) Specific developmental disruption of disrupted-in-schizophrenia-1 function results in schizophrenia-related phenotypes in mice. Proc Natl Acad Sci U S A 104: 18280–18285. Abstract

View all comments by Khaled Rahman

Related News: DISC1: A Matter of Life or Death for Neural Progenitors

Comment by:  Simon Lovestone
Submitted 27 March 2009
Posted 27 March 2009

This is an intriguing paper that builds on a growing body of evidence implicating wnt regulation of GSK3 signaling in psychotic illness (Lovestone et al., 2007).

It is interesting that the authors report that binding of DISC1 to GSK3 results in no change in the inhibitory Ser9 phosphorylation site of GSK3 but a change in Y216 activation site and that this resulted in effects on some but not all GSK3 substrates. This poses a challenge both in terms of understanding the role of GSK3 signaling in schizophrenia and other psychotic disorders and in drug discovery.

The authors cite some of the other evidence for regulation of GSK3 signaling in psychosis, including, for example, the evidence for a role of AKT signaling alteration in schizophrenia and lithium, an inhibitor of GSK3, as a treatment for bipolar disorder. But in both cases, AKT (Cross et al., 1995) and lithium (Jope, 2003), the effect on GSK3 is predominantly via Ser9 phosphorylation and not via Y216. The unstated implication is at least two, possibly three, mechanisms for regulation of GSK3 are all involved in psychotic illness—the auto-phosphorylation at Y216, the exogenous signal transduction regulated Ser9 site inhibition and, if the association of schizophrenia with the wnt inhibitor DKK4 we reported is true (Proitsi et al., 2008), also via the wnt signaling effects on disruption of the macromolecular complex that brings GSK3 together with β-catenin. On the one hand, this might be taken as positive evidence of a role for GSK3 in psychosis—all of its regulatory mechanisms have been implicated; therefore, the case is stronger. On the other hand, GSK3 lies at the intersection point of very many signaling pathways and so is likely to be implicated in many disorders (as it is), and the fact that in cellular and animal models related to psychosis there is no consistent effect on the enzyme is troublesome.

From a drug discovery perspective, those with GSK3 inhibitors in the pipeline will be watching this space carefully. However, it is worth noting that Mao et al. find very selective effects of DISC1 on GSK3 substrates. Despite convincing evidence of an increase in Y216 phosphorylation, which one would expect to increase activity of GSK3 against all substrates, the authors find no evidence of effects on phosphorylation of the GSK3 substrates Ngn2 or C/EBPα. This is somewhat puzzling and merits further attention, especially as in vitro direct binding of a DISC1 fragment to GSK3 inhibited the action of GSK3 on a range of substrates. Might there be more to the direct interaction of DISC1 with GSK3 than a regulation of Y216 autophosphorylation and activation? If, however, GSK3 regulation turns out to be part of the mechanism of schizophrenia or bipolar disorder, then identifying which of the substrates and which of the many activities of GSK3, including on plasticity and hence cognition (Peineau et al., 2007; Hooper et al., 2007), are important in disease will become the critical task.


Lovestone S, Killick R, Di Forti M, Murray R. Schizophrenia as a GSK-3 dysregulation disorder. Trends Neurosci. 2007 Apr 1 ; 30(4):142-9. Abstract

Cross DA, Alessi DR, Cohen P, Andjelkovich M, Hemmings BA. Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. Nature . 1995 Dec 21-28 ; 378(6559):785-9. Abstract

Jope RS. Lithium and GSK-3: one inhibitor, two inhibitory actions, multiple outcomes. Trends Pharmacol Sci . 2003 Sep 1 ; 24(9):441-3. Abstract

Proitsi P, Li T, Hamilton G, Di Forti M, Collier D, Killick R, Chen R, Sham P, Murray R, Powell J, Lovestone S. Positional pathway screen of wnt signaling genes in schizophrenia: association with DKK4. Biol Psychiatry . 2008 Jan 1 ; 63(1):13-6. Abstract

Peineau S, Taghibiglou C, Bradley C, Wong TP, Liu L, Lu J, Lo E, Wu D, Saule E, Bouschet T, Matthews P, Isaac JT, Bortolotto ZA, Wang YT, Collingridge GL. LTP inhibits LTD in the hippocampus via regulation of GSK3beta. Neuron . 2007 Mar 1 ; 53(5):703-17. Abstract

Hooper C, Markevich V, Plattner F, Killick R, Schofield E, Engel T, Hernandez F, Anderton B, Rosenblum K, Bliss T, Cooke SF, Avila J, Lucas JJ, Giese KP, Stephenson J, Lovestone S. Glycogen synthase kinase-3 inhibition is integral to long-term potentiation. Eur J Neurosci . 2007 Jan 1 ; 25(1):81-6. Abstract

View all comments by Simon Lovestone

Related News: DISC1: A Matter of Life or Death for Neural Progenitors

Comment by:  Nick Brandon (Disclosure)
Submitted 27 March 2009
Posted 30 March 2009
  I recommend the Primary Papers

Li-huei Tsai and colleagues have identified another pathway in which the candidate gene DISC1 looks to have a critical regulatory role, namely the wnt signaling pathway, in progenitor cell proliferation. In recent years we have seen that DISC1 has a vital role at the centrosome (Kamiya et al., 2005), in cAMP signaling (Millar et al., 2005), and in multiple steps of adult hippocampal neurogenesis (Duan et al., 2007). They have shown a pivotal role for DISC1 in neural progenitor cell proliferation through regulation of GSK3 signaling using a spectacular combination of cellular and in utero manipulations with shRNAs and GSK3 inhibitor compounds. These findings clearly implicate DISC1 in another “druggable” pathway but at this stage do not really identify new approach/targets, except perhaps to confirm that manipulating adult neurogenesis and the wnt pathway holds much potential hope for therapeutics. Perhaps understanding the mechanism of inhibition of GSK3 by DISC1 in more detail might reveal more novel approaches or encourage more innovative work around this pathway. In addition, I have read the other comment (by Rahman), and though I agree that this work still leaves many questions to be answered, the paper is much more significant and likely reconcilable with previous papers than appreciated. The commentary from Lovestone was very insightful and brings up additional gaps and issues with the present work. Additional experimentation I am sure will tease out more key facets of the DISC1-wnt interaction in the near future.

There are many avenues now to proceed with this work. In particular, from the DISC1-centric view, a GSK3 binding site on DISC1 overlaps with one of the critical core PDE4 binding site. Mao et al. show that residues 211 to 225 are a core part of a GSK3 binding site. Previously, Miles Houslay had shown very elegantly that residues 191-230 form a common binding site (known as common site 1) for both PDE4B and 4D families (Murdoch et al., 2007). It will be important to understand the relationship between GSK3 and PDE4 related signaling in reference to the activity of DISC1 starting at whether a trimolecular complex among DISC1-PDE4-GSK3 can form. Then it will be critical to understand the regulatory interplay among these molecules. For example, it is known that PKA can regulate GSK3 activity (Torii et al., 2008) and the interaction between DISC1 and PDE4, while both GSK3 and PKA can phosphorylate β-catenin (Taurin et al., 2006). The output of these relationships on progenitor proliferation will further deepen insights into the role of DISC1 complexes in neuronal processes. This type of situation is not really surprising for a molecule (DISC1) which has been shown to interact with >100 proteins (Camargo et al., 2007). The context of these interactions in both normal development and disease is likely to be critical to allow understanding of its complete functional repertoire.

Another area where these new findings need to be exploited is in the study of additional animal models. Though the two behavioral endpoint models used in the paper (amphetamine hyperactivity and forced swim test) provide a tantalizing glimpse of the behavioral importance of the complex, it would be critical to look in additional models relevant for schizophrenia and mood disorders. Furthermore, it will be very interesting to look at the effects of GSK3β inhibitors in some of the DISC1 animal models already available and to see if they can reverse all or a subset of reported behaviors. In reviewing a summary of the phenotypes available to date (Shen et al., 2008) there is clearly a number of lines which share the properties with mice injected with DISC1 shRNA into the dentate gyrus and would be of value to look at.

A very exciting paper which I am sure will drive additional research into understanding the role of DISC1 in psychiatry and hopefully encourage drug discovery efforts around this molecular pathway (Wang et al., 2008).


1. 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 1 ; 7(12):1167-78. Abstract

2. Millar JK, Pickard BS, Mackie S, James R, Christie S, Buchanan SR, Malloy MP, Chubb JE, Huston E, Baillie GS, Thomson PA, Hill EV, Brandon NJ, Rain JC, Camargo LM, Whiting PJ, Houslay MD, Blackwood DH, Muir WJ, Porteous DJ. DISC1 and PDE4B are interacting genetic factors in schizophrenia that regulate cAMP signaling. Science . 2005 Nov 18 ; 310(5751):1187-91. Abstract

3. Duan X, Chang JH, Ge S, Faulkner RL, Kim JY, Kitabatake Y, Liu XB, Yang CH, Jordan JD, Ma DK, Liu CY, Ganesan S, Cheng HJ, Ming GL, Lu B, Song H. Disrupted-In-Schizophrenia 1 regulates integration of newly generated neurons in the adult brain. Cell . 2007 Sep 21 ; 130(6):1146-58. Abstract

4. Murdoch H, Mackie S, Collins DM, Hill EV, Bolger GB, Klussmann E, Porteous DJ, Millar JK, Houslay MD. Isoform-selective susceptibility of DISC1/phosphodiesterase-4 complexes to dissociation by elevated intracellular cAMP levels. J Neurosci . 2007 Aug 29 ; 27(35):9513-24. Abstract

5. Torii K, Nishizawa K, Kawasaki A, Yamashita Y, Katada M, Ito M, Nishimoto I, Terashita K, Aiso S, Matsuoka M. Anti-apoptotic action of Wnt5a in dermal fibroblasts is mediated by the PKA signaling pathways. Cell Signal . 2008 Jul 1 ; 20(7):1256-66. Abstract

6. Taurin S, Sandbo N, Qin Y, Browning D, Dulin NO. Phosphorylation of beta-catenin by cyclic AMP-dependent protein kinase. J Biol Chem . 2006 Apr 14 ; 281(15):9971-6. Abstract

7. Camargo LM, Collura V, Rain JC, Mizuguchi K, Hermjakob H, Kerrien S, Bonnert TP, Whiting PJ, Brandon NJ. Disrupted in Schizophrenia 1 Interactome: evidence for the close connectivity of risk genes and a potential synaptic basis for schizophrenia. Mol Psychiatry . 2007 Jan 1 ; 12(1):74-86. Abstract

8. 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

9. Wang Q, Jaaro-Peled H, Sawa A, Brandon NJ. How has DISC1 enabled drug discovery? Mol Cell Neurosci . 2008 Feb 1 ; 37(2):187-95. Abstract

View all comments by Nick Brandon

Related News: DISC1: A Matter of Life or Death for Neural Progenitors

Comment by:  Akira Sawa, SRF Advisor
Submitted 8 April 2009
Posted 8 April 2009

Mao and colleagues’ present outstanding work sheds light on a novel function of DISC1. Because DISC1 is a multifunctional protein, the addition of new functions is not surprising. Thus, for the past several years, the field has focused on how DISC1 can have distinct functions in different cell contexts (for example, progenitor cells vs. postmitotic neurons, or developing cortex vs. adult dentate gyrus). In addition to Mao and colleagues, I understand that several groups, including ours, have obtained preliminary, unpublished evidence that DISC1 regulates progenitor cell proliferation, at least in part via GSK3β. Thus, I am very supportive of this new observation.

If there might be a missing point in this paper, it is unclear whether suppression of GSK3β occurs in several different biological contexts in brain in vivo. In other words, it is uncertain whether DISC1’s actions on GSK3β are constitutive or context-dependent. How can we reconcile differential roles for DISC1 in progenitor cells in contrast to postmitotic neurons? We have already obtained a preliminary promising answer to this question, which is currently being validated very intensively. These two phenotypes (progenitor cell control and postmitotic migration) may compensate for each other in cortical development; thus, overall cortical pathology looks milder in adults, at least in our preliminary unpublished data using DISC1 knockout mice. We are not sure how this novel function of DISC1 may account for the pathology of Scottish cases. Although I have great respect for the Scottish pioneers of DISC1 study, such as St. Clair, Blackwood, and Muir (I believe that the St. Clair et al., 1990 Lancet paper is one of the best publications in psychiatry), now is the time to pay more and more attention to the question of the molecular pathway(s) involving DISC1 in general schizophrenia (see 2009 SRF roundtable discussion). Unlike the role of APP in Alzheimer’s disease, DISC1 is not a key biological target in general schizophrenia, instead being an entry point to explore much more important targets for schizophrenia. There may be no more need to stick to DISC1 itself in the unique Scottish cases in schizophrenia research. In sum, although there may still be key missing points in this study, I wish to congratulate the authors on their outstanding work.


St Clair D, Blackwood D, Muir W, Carothers A, Walker M, Spowart G, Gosden C, Evans HJ. Association within a family of a balanced autosomal translocation with major mental illness. Lancet . 1990 Jul 7 ; 336(8706):13-6. Abstract

View all comments by Akira Sawa

Related News: cAMP Signaling Links Sleep Disturbances and Cognitive Deficits

Comment by:  David J. Porteous, SRF Advisor
Submitted 29 October 2009
Posted 30 October 2009
  I recommend the Primary Papers

This is a really interesting study, which should stimulate new thinking and experimentation. cAMP-dependent signaling is a core component of the mammalian circadian pacemaker (O'Neill et al., 2008). Do those schizophrenic (and indeed non-schizophrenic) patients with sleep disorder show direct evidence for altered PDE4 signaling? If so, does genetic variation in the DISC1-PDE4 complex contribute to this and indicate a differential molecular diagnosis? Clapcote et al. (2007) reported differential effects of Disc1 missense mutations Q31L and L100P on brain PDE4 activity and on behavioral response to rolipram. Do these strains and indeed other Disc1 mutant mice have disturbed sleep patterns?


O'Neill JS, Maywood ES, Chesham JE, Takahashi JS, Hastings MH. cAMP-dependent signaling as a core component of the mammalian circadian pacemaker. Science . 2008 May 16 ; 320(5878):949-53. Abstract

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

View all comments by David J. Porteous

Related News: cAMP Signaling Links Sleep Disturbances and Cognitive Deficits

Comment by:  Robert Stickgold (Disclosure), Dara Manoach
Submitted 2 November 2009
Posted 3 November 2009
  I recommend the Primary Papers

Although disturbed sleep is a prominent feature of schizophrenia that has been recognized since Kraepelin (1919), its relation to the pathophysiology, signs, and symptoms of schizophrenia remains poorly understood. In healthy individuals, there is now overwhelming evidence that critical aspects of learning and memory consolidation depend on sleep. Yet, in spite of the ubiquity of sleep disorders in schizophrenia, they have generally been overlooked as a potential contributor to cognitive deficits. As recently reviewed by Manoach and Stickgold (2009), an emerging literature suggests that abnormal sleep in schizophrenia may contribute to these cognitive deficits through its impairment of sleep-dependent memory consolidation.

The finding by Vecsey et al. that sleep deprivation leads to an increase in transcription and translation of the gene coding for phosphodiesterase-4 (PDE4), and that inhibiting the action of PDE4 with the drug rolipram restores both normal cAMP levels and sleep-dependent memory consolidation in rodents, raises the question of whether rolipram could also restore sleep-dependent memory consolidation in individuals with schizophrenia. Manoach and her colleagues have published a pair of papers (Manoach et al., 2004; 2009) demonstrating that while schizophrenia patients show normal learning of a finger tapping motor sequence task (MST) during an initial training session, they fail to show the significant increase in speed that reliably develops across a night of sleep in healthy individuals (Walker et al., 2002). In these papers, they suggest that the failure of overnight consolidation may be related to a deficit in sleep spindles (Ferrarelli et al., 2007; Manoach et al., 2009), a characteristic EEG signature of non-REM sleep, which have been proposed to mediate memory consolidation in general (Sejnowski and Destexhe, 2000), and which have been shown to correlate with overnight improvement on the MST in particular (Nishida and Walker, 2007).

But the new findings of Vecsey et al. suggest another possibility, namely an overactive PDE4 system in schizophrenia. As others have noted here, some PDE4 isoforms bind to the normal form of the schizophrenia susceptibility gene DISC1, forming an inactive DISC1-PDE4 complex. If this inactivation fails in schizophrenia, then the normal sleep-dependent suppression of PDE4 activity may similarly fail, as PDE4 activity remains at inappropriately high levels. In other words, the failure of sleep-dependent memory consolidation in schizophrenia reported by Manoach et al. (2004, 2009) may be a consequence of the disrupted regulation of PDE4.

The experimental test of this hypothesis is quite simple and straightforward: Administration of rolipram, after initial MST training but prior to sleep (along with a possible second dose later in the night), should restore normal sleep-dependent enhancement of MST performance.


Ferrarelli F, Huber R, Peterson MJ, Massimini M, Murphy M, Riedner BA, Watson A, Bria P, Tononi G. Reduced sleep spindle activity in schizophrenia patients. Am J Psychiatry. 2007;164(3):483-92. Abstract

Kraepelin E. Dementia praecox and paraphrenia (R. Barclay, Trans.). 1919. Edinburgh, Scotland: ES Livingston.

Manoach DS, Thakkar KN, Stroynowski E, Ely A, McKinley SK, Wamsley E, Djonlagic I, Vangel MG, Goff DC, Stickgold R. Reduced overnight consolidation of procedural learning in chronic medicated schizophrenia is related to specific sleep stages. J Psychiatr Res. 2009 Aug 7. Abstract

Manoach DS, Cain MS, Vangel MG, Khurana A, Goff DC, Stickgold R. A failure of sleep-dependent procedural learning in chronic, medicated schizophrenia. Biol Psychiatry. 2004;56:951-6. Abstract

Manoach DS, Stickgold R. Does abnormal sleep impair memory consolidation in schizophrenia? Front Hum Neurosci. 2009;3:21. Abstract

Nishida M, Walker MP. Daytime naps, motor memory consolidation and regionally specific sleep spindles. PLoS ONE. 2007;2(4):e341. Abstract

Sejnowski TJ, Destexhe A. Why do we sleep? Brain Res. 2000;886(1-2): 208-23. Abstract

Walker MP, Brakefield T, Morgan A, Hobson JA, Stickgold R. Practice with sleep makes perfect: sleep-dependent motor skill learning. Neuron. 2002;35(1):205-11. Abstract

View all comments by Robert Stickgold
View all comments by Dara Manoach

Related News: DISC1 and SNAP23 Emerge In NMDA Receptor Signaling

Comment by:  Jacqueline Rose
Submitted 2 March 2010
Posted 2 March 2010
  I recommend the Primary Papers

The newly published paper by Katherine Roche and Paul Roche reports SNAP-23 expression in neuron dendrites and examines the possible role of this neuronal SNAP-23 protein. To this point, SNAP-23 has traditionally been discussed in reference to vesicle trafficking in epithelial cells (see Rodriguez-Boulan et al., 2005 for review), so it is of interest to determine the function of SNAP-23 in neurons. Suh et al. report that surface NMDA receptor expression and NMDA-mediated currents are inhibited following SNAP-23 knockdown. Further, SNAP-23 knockdown results in a specific decrease in NR2B subunit insertion; previously, the NR2B subunit has been reported to preferentially localize to recycling endosomes compared to NR2A (Lavezzari et al., 2004). Given these findings, it is reasonable to conclude that SNAP-23 may be involved in maintaining NMDA receptor surface expression possibly by binding to NMDA-specific recycling endosomes.

Interestingly, there is recent evidence that PKC-induced NMDA receptor insertion is mediated by another neuronal SNARE protein; postsynaptic SNAP-25 (Lau et al., 2010). It is possible that activity-induced NMDA receptor trafficking is mediated by SNAP-25, while baseline maintenance of NMDA receptor levels relies on SNAP-23. Other evidence to suggest a strictly regulatory role for SNAP-23 in neuronal NMDA insertion is the finding that activity-dependent receptor insertion from early endosomes has previously been reported to be restricted to AMPA-type glutamate receptors (Park et al., 2004). However, it is possible that activity-induced insertion of AMPA receptors occurs via a distinct endosome pool than NMDA receptors; AMPA and NMDA receptor trafficking has been reported to proceed by distinct vesicle trafficking pathways (Jeyifous et al., 2009).

Although SNAP-23 may not be involved in activity-dependent early endosome receptor trafficking, it is possible that SNAP-23 operates in other pathways linked to activity-induced NMDA receptor trafficking. For instance, SNAP-23 may be the SNARE protein by which lipid raft shuttling of NMDA receptors occurs. SNAP-23 has been found to preferentially associate with lipid rafts over SNAP-25 in PC12 cells (Salaün et al., 2005). As well, NMDA receptors have been found to associate with lipid raft associated proteins flotilin-1 and -2 in neurons (Swanwick et al., 2009). Lipid raft trafficking of NMDA receptors to post-synaptic densities has been reported to follow global ischemia (Besshoh et al., 2005), and the possibility remains that under certain circumstances, NMDA trafficking occurs by lipid raft association to SNAP-23.

Taken together, the discovery of post-synaptic SNARE proteins offers several avenues of research to determine their roles and functions in glutamatergic synapse organization. Further, investigating disruption of synaptic receptor organization presents several possibilities for potential etiologies of disorders linked to compromised glutamate signaling like schizophrenia.


Besshoh, S., Bawa, D., Teves, L., Wallace, M.C. and Gurd, J.W. (2005). Increased phosphorylation and redistribution of NMDA receptors between synaptic lipid rafts and post-synaptic densities following transient global ischemia in the rat brain. Journal of Neurochemistry, 93: 186-194. Abstract

Jeyifous, O., Waites, C.L., Specht, C.G., Fujisawa, S., Schubert, M., Lin, E.I., Marshall, J., Aoki, C., de Silva, T., Montgomery, J.M., Garner, C.C. and Green, W.N. (2009). SAP97 and CASK mediate sorting of NMDA receptors through a previously unknown secretory pathway. Nature Neuroscience, 12: 1011-1019. Abstract

Lau, C.G., Takayasu, Y., Rodenas-Ruano, A., Paternain, A.V., Lerma, J., Bennet, M.V.L. and Zukin, R.S. (2010). SNAP-25 is a target of protein kinase C phosphorylation critical to NMDA receptor trafficking. Journal of Neuroscience, 30: 242-254. Abstract

Lavezzari, G., McCallum, J., Dewey, C.M. and Roche, K.W. (2004). Subunit-specific regulation of NMDA receptor endocytosis. Journal of Neuroscience, 24: 6383-6391. Abstract

Park, M., Penick, E.C., Edward, J.G., Kauer, J.A. and Ehlers, M.D. (2004). Recycling endosomes supply AMPA receptors for LTP. Science, 305: 1972-1975. Abstract

Rodriguez-Boulan, E., Kreitzer, G. and Müsch, A. (2005) Organization of vesicular trafficking in epithelia. Nature Reviews: Molecular Cell Biology, 6: 233-247. Abstract

Salaün, C., Gould, G.W. and Chamberlain, L.H. (2005). The SNARE proteins SNAP-25 and SNAP-23 display different affinities for lipid rafts in PC12 cells. Journal of Biological Chemistry, 280: 1236-1240. Abstract

Suh, Y.H., Terashima, A., Petralia, R.S., Wenthold, R.J., Isaac, J.T.R., Roche, K.W. and Roche, P.A. (2010). A neuronal role for SNAP-23 in postsynaptic glutamate receptor trafficking. Nat Neurosci. 2010 Mar;13(3):338-43. Abstract

Swanwick, C.C., Shapiro, M.E., Chang, Y.Z. and Wenthold, R.J. (2009). NMDA receptors interact with flotillin-1 and -2, lipid raft-associated proteins. FEBS Letters, 583: 1226-1230. Abstract

View all comments by Jacqueline Rose

Related News: New Details About DISC1’s Role in Cellular Compartments Emerge

Comment by:  Verian Bader
Submitted 1 June 2012
Posted 1 June 2012

A couple of recently published papers have provided insights into the cell physiology of DISC1. Although DISC1 is one of the most extensively studied susceptibility genes for psychiatric illness, the promoter of DISC1 has not been characterized so far. In a systematic approach based on luciferase reporter genes, Walker et al. (Walker et al., 2012) describe a repressive and an enhancing promoter region upstream of the transcription start. The DISC1 promoter is negatively regulated by FOXP2; hence, affected FOXP2 mutation carriers might show a higher DISC1 expression. Therefore, it would be interesting to know if these FOXP2 mutation carriers also display a higher level of insoluble DISC1, since increased expression leads to an increase of insoluble DISC1 (Leliveld et al., 2008). As a result, and possibly through aggregation, DISC1 loses its ability to bind to specific interaction partners, thereby disrupting some cellular pathways (Atkin et al., 2012) and potentially leading to other gain-of-function effects. In this context, Malavasi et al. (Malavasi et al., 2012) report in detail on the control of DISC1 over the transcriptional activity of ATF4. ATF4 itself acts as a key protein in emotional learning and memory via its ability to repress CREB activity. The authors provide intriguing results on how full-length DISC1 protein and its non-synonymous polymorphisms 37W and 607F differentially inhibit ATF4 activity by distinct mechanisms. Both genetic variants—the rare, putatively causal substitution 37W and the common variant 607F—exclude the protein from the nucleus, thereby reducing ATF4 inhibition.

Eykelenboom et al. (Eykelenboom et al., 2012) also report on an abnormal subcellular distribution of mutated DISC1 by elegantly expanding the concept of DISC1 translocation-derived fusion proteins proposed previously (Zhou et al., 2008; Zhou et al., 2010). This is the first paper to confirm the existence of three different transcripts from the translocated DISC1 gene, potentially giving rise to DISC1 proteins adding 1, 60 or 69 amino acids to the N-terminus (1-597). Upon biophysical characterization, the two larger proteins termed CP60 and CP69 exhibit a higher helical amount and larger protein assemblies. When the recombinant fusion proteins were expressed in cells, they mediated abnormal mitochondrial localization and altered mitochondrial membrane potential.

The last two publications show that altered DISC1 protein structure, ranging from single amino acid changes to large, chimeric fusion proteins, can culminate in changes of the protein cellular distribution, oligomerization status, and abnormal cellular function. Increasing evidence suggests that defined DISC1 protein species have particular local functions within the neuron or glia cells, and that at least a part of the DISC1-mediated pathology is dependent on abnormal cellular distribution of the protein.


Atkin TA, Brandon NJ, Kittler JT. Disrupted in Schizophrenia 1 forms pathological aggresomes that disrupt its function in intracellular transport. Hum Mol Genet . 2012 May 1 ; 21(9):2017-28. Abstract

Eykelenboom JE, Briggs GJ, Bradshaw NJ, Soares DC, Ogawa F, Christie S, Malavasi EL, Makedonopoulou P, Mackie S, Malloy MP, Wear MA, Blackburn EA, Bramham J, McIntosh AM, Blackwood DH, Muir WJ, Porteous DJ, Millar JK. A t(1;11) translocation linked to schizophrenia and affective disorders gives rise to aberrant chimeric DISC1 transcripts that encode structurally altered, deleterious mitochondrial proteins. Hum Mol Genet . 2012 May 16. Abstract

Leliveld SR, Bader V, Hendriks P, Prikulis I, Sajnani G, Requena JR, Korth C. Insolubility of disrupted-in-schizophrenia 1 disrupts oligomer-dependent interactions with nuclear distribution element 1 and is associated with sporadic mental disease. J Neurosci . 2008 Apr 9 ; 28(15):3839-45. Abstract

Malavasi EL, Ogawa F, Porteous DJ, Millar JK. DISC1 variants 37W and 607F disrupt its nuclear targeting and regulatory role in ATF4-mediated transcription. Hum Mol Genet . 2012 Jun 15 ; 21(12):2779-92. Abstract

Walker RM, Hill AE, Newman AC, Hamilton G, Torrance HS, Anderson SM, Ogawa F, Derizioti P, Nicod J, Vernes SC, Fisher SE, Thomson PA, Porteous DJ, Evans KL. The DISC1 promoter: characterization and regulation by FOXP2. Hum Mol Genet . 2012 Apr 4. Abstract

Zhou X, Geyer MA, Kelsoe JR. Does disrupted-in-schizophrenia (DISC1) generate fusion transcripts? Mol Psychiatry . 2008 Apr ; 13(4):361-3. Abstract

Zhou X, Chen Q, Schaukowitch K, Kelsoe JR, Geyer MA. Insoluble DISC1-Boymaw fusion proteins generated by DISC1 translocation. Mol Psychiatry . 2010 Jul 1 ; 15(7):669-72. Abstract

View all comments by Verian Bader

Related News: New Role for DISC1 in mRNA Transport

Comment by:  Toshi Tomoda
Submitted 11 April 2015
Posted 14 April 2015

I was puzzled by cortical migration data presented in a recent paper from the Kaibuchi lab, where shRNA targeting DISC1 exon 2 caused defective migration of cortical neurons in mice lacking exon 2 of the gene. This appears to be a basis for the researchers' claim that migration deficits previously shown by DISC1 knockdown must have been off-target effects of the shRNA used. If this was indeed the case, then all other shRNAs, which consistently demonstrated the developmental role of DISC1 in neuronal migration in the past literatures, need to be re-examined.

But, what about a previous paper published by them, including the Kamiya lab and the Nakajima lab (Kubo et al., 2010), where they used multiple shRNAs against DISC1, as well as respective rescue constructs, and unanimously concluded that DISC1 has a role in cortical migration and comprehensively showed delayed migration at a specific developmental time point after DISC1 knockdown? Could all that be due to off-target effects?

To resolve this discrepancy, one should obviously observe the DISC1 knockout phenotype in an unbiased manner and determine if delayed migration can be seen. To our great surprise, this has never been carefully done yet with this DISC1 exon 2/3 deletion mouse, using, for example, a simple BrdU-birth-dating experiment. In fact, in the supplementary data in the paper by Tsuboi et al., cortical migration in DISC1 mutant mice appears to be delayed as compared with wild-type controls. Detailed quantification data are missing, so we cannot say if my impression can be validated or not, but I think one should simply look at DISC1 mutant phenotype naively before we can conclude anything regarding the developmental role of DISC1 in cortical migration. If the knockout mice have a delayed migration phenotype, it makes no sense to discuss the off-target effect issue in the first place.


Kubo K, Tomita K, Uto A, Kuroda K, Seshadri S, Cohen J, Kaibuchi K, Kamiya A, Nakajima K. Migration defects by DISC1 knockdown in C57BL/6, 129X1/SvJ, and ICR strains via in utero gene transfer and virus-mediated RNAi. Biochem Biophys Res Commun. 2010 Oct 1; 400(4):631-7. Abstract

View all comments by Toshi Tomoda

Related News: New Role for DISC1 in mRNA Transport

Comment by:  Ken-ichiro Kubo
Submitted 12 April 2015
Posted 17 April 2015

In their recent paper, Tsuboi and colleagues write that "the DISC1-/- mouse displays no gross abnormalities in the brain's cytoarchitecture, whereas DISC1 knockdown caused severe neurodevelopmental abnormalities, including neurogenesis and cell migration. This phenotypic discrepancy between DISC1-/- and DISC1-knockdown mice may be explained by off-target effects of short hairpin RNAs (shRNAs)."

However, I am afraid that this statement by the authors, which simply concludes that off-target effects explain these scientifically mysterious but interesting results, is inappropriate.

First, it is important to compare the differences between the phenotypes induced by the knockdown and the phenotypes induced by the knockdown and the simultaneous co-expression of a knockdown-resistant form of the target protein (Heng et al., 2008; Sekine et al., 2012; Fang et al., 2013). In the case of DISC1, different laboratories have independently proved that the migration defects caused by DISC1-knockdown were significantly normalized by the co-expression of knockdown-resistant wild-type DISC1 protein (Ishizuka et al., 2011; Singh et al., 2011; Kubo et al., 2010). Although off-target effects are a very important consideration in the RNAi approach, the rescued phenotypes should be specifically attributed to the functions of the recovered protein.

Second, in order to clarify the phenotypic discrepancy between knockout and knockdown that is often observed, detailed and systematic analysis is necessary to depict the subtle abnormal cytoarchitecture of the knockout mice because of redundancy and compensation mechanisms (Sekine et al., 2012; Namba et al., 2014). Even in their DISC1Delta2-3/Delta2-3 mice (Kuroda et al., 2011; Tsuboi et al., 2015), when they electroporated control vectors at E15 and analyzed brains at P1 (Tsuboi et al., 2015, Supplementary Figure 13), ectopic neurons in the white matter seem to be increased, in spite of a decrease in the number of migrated neurons in the top of the neocortex compared to the wild-type mice, suggesting the possibility of subtle migration defects in their DISC1Delta2-3/Delta2-3 mice.

Moreover, we have previously reported that the developmental migration delay induced by the DISC1 knockdown was relatively overcome and masked by the time the mice were adults (Kubo et al., 2010; Tomita et al., 2011). Detailed analysis of the final distribution is required: for example, the relative distribution of the early-born neurons and late-born neurons should be analyzed by using sequential labeling of neurons to find altered final distribution even if no gross abnormality is observed at the adult stage (Kubo et al., 2010; Sekine et al., 2011; Sekine et al., 2012).

Third, ideally, the phenotypes induced by the expression of Cre protein in conditional knockout mice should be compared to define cell-autonomous acute knockout/knockdown effects (Heng et al., 2008; Franco et al., 2011; Morgan-Smith et al., 2014; Ohtaka-Maruyama et al., 2013). The conditional knockout system is desirable to prevent off-target effects. But even in this system, the phenotypes should be carefully considered because of the residual protein that is produced before the occurrence of Cre-mediated recombination. Analysis using the conditional knockout system is a necessary future experiment in the field of DISC1 study.

Taken together, multiple laboratories have established that migration failure is caused by DISC1 knockdown and that the knockdown phenotype is specifically rescued by the co-expression of knockdown-resistant wild-type DISC1 protein. Although the mechanisms of DISC1 expression and its role in neuronal migration have not been completely uncovered yet, it is clear that DISC1 is indeed involved in cortical neuronal migration. Further detailed analysis, such as sequential labeling of neurons, may be required to detect the subtle abnormal cytoarchitecture in the knockout mice. Analysis using the conditional knockout system is also required.

We must admit that some important questions about this gene remain to be clarified. I believe these issues need to be left as an open question at this point. I excitedly await future studies on DISC1 to help us understand this interesting molecule.


Fang WQ, Chen WW, Fu AK, Ip NY. Axin directs the amplification and differentiation of intermediate progenitors in the developing cerebral cortex. Neuron. 2013 Aug 21; 79(4):665-79. Abstract

Franco SJ, Martinez-Garay I, Gil-Sanz C, Harkins-Perry SR, Müller U. Reelin regulates cadherin function via Dab1/Rap1 to control neuronal migration and lamination in the neocortex. Neuron. 2011 Feb 10; 69(3):482-97. Abstract

Heng JI, Nguyen L, Castro DS, Zimmer C, Wildner H, Armant O, Skowronska-Krawczyk D, Bedogni F, Matter JM, Hevner R, Guillemot F. Neurogenin 2 controls cortical neuron migration through regulation of Rnd2. Nature. 2008 Sep 4; 455(7209):114-8. Abstract

Ishizuka K, Kamiya A, Oh EC, Kanki H, Seshadri S, Robinson JF, Murdoch H, Dunlop AJ, Kubo K, Furukori K, Huang B, Zeledon M, Hayashi-Takagi A, Okano H, Nakajima K, Houslay MD, Katsanis N, Sawa A. DISC1-dependent switch from progenitor proliferation to migration in the developing cortex. Nature. 2011 May 5; 473(7345):92-6. Abstract

Kubo K, Tomita K, Uto A, Kuroda K, Seshadri S, Cohen J, Kaibuchi K, Kamiya A, Nakajima K. Migration defects by DISC1 knockdown in C57BL/6, 129X1/SvJ, and ICR strains via in utero gene transfer and virus-mediated RNAi. Biochem Biophys Res Commun. 2010 Oct 1; 400(4):631-7. Abstract

Kuroda K, Yamada S, Tanaka M, Iizuka M, Yano H, Mori D, Tsuboi D, Nishioka T, Namba T, Iizuka Y, Kubota S, Nagai T, Ibi D, Wang R, Enomoto A, Isotani-Sakakibara M, Asai N, Kimura K, Kiyonari H, Abe T, Mizoguchi A, Sokabe M, Takahashi M, Yamada K, Kaibuchi K. Behavioral alterations associated with targeted disruption of exons 2 and 3 of the Disc1 gene in the mouse. Hum Mol Genet. 2011 Dec 1; 20(23):4666-83. Abstract

Morgan-Smith M, Wu Y, Zhu X, Pringle J, Snider WD. GSK-3 signaling in developing cortical neurons is essential for radial migration and dendritic orientation. Elife. 2014; 3():e02663. Abstract

Namba T, Kibe Y, Funahashi Y, Nakamuta S, Takano T, Ueno T, Shimada A, Kozawa S, Okamoto M, Shimoda Y, Oda K, Wada Y, Masuda T, Sakakibara A, Igarashi M, Miyata T, Faivre-Sarrailh C, Takeuchi K, Kaibuchi K. Pioneering axons regulate neuronal polarization in the developing cerebral cortex. Neuron. 2014 Feb 19; 81(4):814-29. Abstract

Ohtaka-Maruyama C, Hirai S, Miwa A, Heng JI, Shitara H, Ishii R, Taya C, Kawano H, Kasai M, Nakajima K, Okado H. RP58 regulates the multipolar-bipolar transition of newborn neurons in the developing cerebral cortex. Cell Rep. 2013 Feb 21; 3(2):458-71. Abstract

Sekine K, Honda T, Kawauchi T, Kubo K, Nakajima K. The outermost region of the developing cortical plate is crucial for both the switch of the radial migration mode and the Dab1-dependent "inside-out" lamination in the neocortex. J Neurosci. 2011 Jun 22; 31(25):9426-39. Abstract

Sekine K, Kawauchi T, Kubo K, Honda T, Herz J, Hattori M, Kinashi T, Nakajima K. Reelin controls neuronal positioning by promoting cell-matrix adhesion via inside-out activation of integrin alpha5beta1. Neuron. 2012 Oct 18; 76(2):353-69. Abstract

Singh KK, De Rienzo G, Drane L, Mao Y, Flood Z, Madison J, Ferreira M, Bergen S, King C, Sklar P, Sive H, Tsai LH. Common DISC1 polymorphisms disrupt Wnt/GSK3ß signaling and brain development. Neuron. 2011 Nov 17; 72(4):545-58. Abstract

Tomita K, Kubo K, Ishii K, Nakajima K. Disrupted-in-Schizophrenia-1 (Disc1) is necessary for migration of the pyramidal neurons during mouse hippocampal development. Hum Mol Genet. 2011 Jul 15; 20(14):2834-45. Abstract

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