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New Details About DISC1’s Role in Cellular Compartments Emerge

18 May 2012. The many functions of the famous psychiatric disorder risk gene, disrupted in schizophrenia 1 (DISC1), continue to be revealed. In a trio of studies from the University of Edinburgh in the United Kingdom, all published in Human Molecular Genetics, researchers explore the promoter region DISC1 and shed light on new mechanisms that may underlie DISC1-mediated dysfunction in psychiatric illnesses, including roles in mitochondria and the nucleus.

The scaffolding protein DISC1 first entered the schizophrenia arena when a chromosomal translocation that disrupts the gene was discovered in a Scottish family fraught with mental illness. The function of DISC1 in both health and disease has since been enthusiastically studied, with new papers appearing regularly (see SRF related news story). At this point, one thing is very clear—DISC1 plays a variety of roles in a number of important brain processes, including neurogenesis (see SRF related news story), neuronal development, signaling, spine regulation, and synaptic function (Brandon and Sawa, 2011). These three studies add to this growing pile of evidence that DISC1 is a critical cellular component.

Mitochondrial misfits
In one study, published online April 30, J. Kirsty Millar and colleagues used lymphoblastoid cell lines from translocation carriers, who exhibit 50 percent lower expression of DISC1 (see SRF related news story), to show that the translocation results in the production of abnormal transcripts and proteins, causing severe mitochondrial dysfunction. The problem arises when DISC1 fuses with the chromosome 11 gene DISC1 fusion partner 1 (DISC1FP1), resulting in chimeric proteins consisting of exons 1-8 of the DISC1 sequence, plus one, 60, or 69 amino acids (termed CP1, CP60, and CP69, respectively).

First author Jennifer Eykelenboom and colleagues found that the additional 69 amino acids in CP69 modify the protein’s secondary structure, resulting in a higher α-helical content and the formation of large, stable protein assemblies. The authors speculate that these might be responsible for the DISC1 aggregates that have been observed in postmortem tissue from patients with mental illness (Corth et al., 2009), and predict a similar situation for CP60. In addition, in both cell lines and primary neuronal cultures, CP60 and CP69 were mainly targeted to mitochondria, and their expression altered mitochondrial morphology by inducing clustering and leading to a loss of mitochondrial membrane potential. Thus, these chimeric proteins induce severe mitochondrial dysfunction. Future studies are needed to confirm the effects of CP60 and CP69 in brain tissue from translocation carriers.

Trouble targeting the nucleus
In a second study led by Millar, published online March 28, first author Elise Malavasi and colleagues detailed a role for schizophrenia risk variants in DISC1 in its distribution in another cellular compartment—the nucleus. They found that a rare variant termed 37W, as well as a more common one known as 607F, both prevent targeting of DISC1 to the nucleus in a dominant-negative fashion. In addition, the researchers demonstrated that DISC1 inhibits the activity of transcription factor ATF4, known to be upregulated in response to cellular stress, suggestive of a role for DISC1 in transcriptional regulation. This effect of DISC1 was attenuated in carriers of 37W and 607F. In fact, DISC1 overexpression decreased CRE-dependent transcription in response to endoplasmic reticulum stress, and this effect was again diminished in the risk variant carriers.

“DISC1 functions as a hub protein whose principal role is to modulate various cellular processes…," Malavasi and colleagues write. "Sequence changes in DISC1 that disrupt its normal compartmentalization and protein interactions are therefore likely to have functional consequences, and may highlight biological processes involved in psychopathology.”

Probing the promoter
In a third study, published online April 4 and led by Rosie Walker, researchers characterized the promoter region of DISC1, finding that it lacked many of the common components of other promoter regions, such as a TATA box, initiator, and downstream promoter element. The researchers did identify a region upstream from the transcription start site that increases promoter activity, as well as one further upstream that decreases it. Walker and colleagues also found that DISC1 promoter activity, and protein levels, are inhibited by the transcription factor FOXP2. Of note, mutations in FOXP2 lead to a genetic form of developmental verbal dyspraxia, a disorder of speech and language (Lai et al., 2001). The authors reported that two of these mutations reduce the inhibitory effect of FOXP2 on DISC1 promoter activity, providing “a point of molecular convergence between neurodevelopmental disorders that have traditionally been viewed as diagnostically distinct.”—Allison A. Curley.

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 Apr 30. 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

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 Mar 28. Abstract

Comments on News and Primary Papers

Primary Papers: 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.

Comment by:  Karoly Mirnics, SRF Advisor
Submitted 21 May 2012
Posted 21 May 2012

DISC1 is a well-established gene conferring schizophrenia susceptibility in a subset of patients. This is a multifunctional protein, involved in regulation of neuronal progenitor cell proliferation and migration, and modulation of dendritic spines. This new study highlights a novel role of this gene vis-à-vis pathophysiology of schizophrenia: translocation of the DISC1 gene to a gene on chromosome 11, DISC1 fusion partner 1 (DISC1FP1), results in the production of various aberrant chimeric transcripts with novel protein-coding potential. This results in the formation of abnormally large protein assemblies that exhibit increased thermal stability, and these abnormal chimeric proteins have a potential to induce abnormal mitochondrial morphology and abolish mitochondrial membrane potential.

We have known for more than a decade that mitochondrial dysfunction/energy metabolism in schizophrenia and bipolar disorder appear to be an integral part of the disease process, but to date it remains unclear if these changes are primary and whether they directly contribute to the disease process/symptomatology—or if they are just a downstream consequence of accelerated synaptic pruning or oligodendrocyte deficits. The current findings could suggest that mitochondrial deficits are a conversion point for the action of various mutations, and that this will have to be investigated in postmortem brains of diseased subjects.

View all comments by Karoly Mirnics

Primary Papers: DISC1 variants 37W and 607F disrupt its nuclear targeting and regulatory role in ATF4-mediated transcription.

Comment by:  Karoly Mirnics, SRF Advisor
Submitted 21 May 2012
Posted 21 May 2012

The authors report that both the rare DISC1 variant 37W and the common variant 607F independently disrupt DISC1 nuclear targeting. Under normal conditions, wild-type DISC1 inhibits the transcriptional activity of ATF4, but this dampening effect is weakened in DISC1 variants 37W and 607F. Furthermore, expression of these schizophrenia-associated disease variants increases endoplasmic reticulum stress levels. It is important to point out that this study found that a putatively causal DISC1 variant (37W) and the common variant (607F) both perturb the nuclear targeting of wild-type DISC1 in a dominant-negative fashion.

It is also noteworthy that previous postmortem studies have found increased chaperone expression in schizophrenia, and while this finding might not have been a direct result of DISC1 genetic variants, it argues that increased cellular stress could be a convergent, critical molecular mechanism characteristic of schizophrenia. This mechanism can clearly arise from multiple genetic vulnerabilities. However, as the majority of people who carry the common variant 607F do not develop the disease, it will be important to establish which additional genetic and/or environmental factors can "potentiate" the stress effects of this variant. Furthermore, this study strongly underscores the need for various assessments on the common variant 607F carriers, as understanding the functioning of this variant and its effects on brain processes might be critical knowledge for understanding schizophrenia.

View all comments by Karoly MirnicsComment 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

Comments on Related News

Related News: Messing with DISC1 Protein Disturbs Development, and More

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

Related News: Messing with DISC1 Protein Disturbs Development, and More

Comment 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 Nairn

Related News: Messing with DISC1 Protein Disturbs Development, and More

Comment by:  Patricia Estani
Submitted 2 January 2006
Posted 2 January 2006
  I recommend the Primary Papers

Related News: Messing with DISC1 Protein Disturbs Development, and More

Comment by:  Ali Mohammad Foroughmand
Submitted 16 December 2006
Posted 16 December 2006
  I recommend the Primary Papers

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

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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: 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

View all comments by Ken-ichiro Kubo