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...  Read more

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.

References:
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).

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

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...  Read more

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.

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...  Read more

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.

References:

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

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...  Read more

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.

References:

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

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...  Read more

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.

References:

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

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...  Read more

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).

References:

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

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...  Read more

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.

References:

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

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...  Read more

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).

References:

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

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...  Read more

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.

References:

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

The seminal identification of mutations in DISC1 associated with schizophrenia and other psychiatric disorders raises several obvious questions: what does the DISC1 protein normally do? What are its biochemical and cellular functions, and what processes are affected by its mutation? How do defects in these cellular processes ultimately lead to altered brain function and psychopathology? Which brain systems are affected and how? Similar questions could be asked for the growing number of other genes that have been implicated by the identification of putatively causal mutations, including NRG1, ERBB4, NRXN1, CNTNAP2, and many copy number variants. Finding the points of biochemical or phenotypic convergence for these proteins or mutations may be key to understanding how mutations in so many different genes can lead to a similar clinical phenotype and to suggesting points of common therapeutic intervention.

The papers by Kim et al. and Enomoto et al. add more detail to the complex picture of the biochemical interactions of DISC1 and its diverse cellular functions. The links...  Read more

The seminal identification of mutations in DISC1 associated with schizophrenia and other psychiatric disorders raises several obvious questions: what does the DISC1 protein normally do? What are its biochemical and cellular functions, and what processes are affected by its mutation? How do defects in these cellular processes ultimately lead to altered brain function and psychopathology? Which brain systems are affected and how? Similar questions could be asked for the growing number of other genes that have been implicated by the identification of putatively causal mutations, including NRG1, ERBB4, NRXN1, CNTNAP2, and many copy number variants. Finding the points of biochemical or phenotypic convergence for these proteins or mutations may be key to understanding how mutations in so many different genes can lead to a similar clinical phenotype and to suggesting points of common therapeutic intervention.

The papers by Kim et al. and Enomoto et al. add more detail to the complex picture of the biochemical interactions of DISC1 and its diverse cellular functions. The links with Akt and PTEN signaling are especially interesting, given the previous implication of these proteins in schizophrenia and autism. Akt, in particular, may provide a link between Nrg1/ErbB4 signaling and DISC1 intracellular functions.

These studies also reinforce the importance of DISC1 and its interacting partners in neurodevelopment, specifically in cell migration and axonal extension. In particular, they highlight the roles of these proteins in postnatal hippocampal development and adult hippocampal neurogenesis. They also raise the question of which extracellular signals and receptors regulate these processes through these signalling pathways. The Nrg1/ErbB4 pathway has already been implicated, but there are a multitude of other cell migration and axon guidance cues known to regulate hippocampal development, some of which, for example, semaphorins, signal through the PTEN pathway.

Whether or how disruptions in these developmental processes contribute to psychopathology also remains unclear. It seems likely that the effects of mutations in any of these genes will be highly pleiotropic and have effects in many brain systems. The reported pathology in schizophrenia is not restricted to hippocampus but extends to cortex, thalamus, cerebellum, and many other regions. Similarly, while the cognitive deficits receive a justifiably large amount of attention, given that they may have the most clinical impact, motor and sensory deficits are also a stable and consistent part of the syndrome that must be explained. Pleiotropic effects on prenatal and postnatal development, as well as on adult processes, may actually be the one common thread characterizing the genes so far implicated. These new papers represent the first steps in the kinds of detailed biological studies that will be required to make explanatory links from mutations, through biochemical and cellular functions, to effects on neuronal networks and ultimately psychopathology.

DISC1 disruption by chromosomal translocation cosegregates with several neuropsychiatric disorders, including schizophrenia (Blackwood et al., 2001; Millar et al., 2000). Recent attention has focused on the effects of DISC1 on the structure and function of the dentate gyrus, one of the few brain regions that exhibit neurogenesis throughout life. The downregulation of DISC1 has several deleterious effects on the dentate gyrus, including aberrant neuronal migration (Duan et al., 2007). However, the mechanisms through which DISC1 regulates the structure and function of the dentate gyrus remain unknown. The dentate gyrus and its output to the CA3 area, the mossy fiber, show several abnormalities in schizophrenia and other neuropsychiatric diseases (Kobayashi, 2009). Thus, understanding how a gene associated with neuropsychiatric disease, DISC1, mechanistically impacts the dentate gyrus is an...  Read more

DISC1 disruption by chromosomal translocation cosegregates with several neuropsychiatric disorders, including schizophrenia (Blackwood et al., 2001; Millar et al., 2000). Recent attention has focused on the effects of DISC1 on the structure and function of the dentate gyrus, one of the few brain regions that exhibit neurogenesis throughout life. The downregulation of DISC1 has several deleterious effects on the dentate gyrus, including aberrant neuronal migration (Duan et al., 2007). However, the mechanisms through which DISC1 regulates the structure and function of the dentate gyrus remain unknown. The dentate gyrus and its output to the CA3 area, the mossy fiber, show several abnormalities in schizophrenia and other neuropsychiatric diseases (Kobayashi, 2009). Thus, understanding how a gene associated with neuropsychiatric disease, DISC1, mechanistically impacts the dentate gyrus is an important question with much clinical relevance.

The recent papers by Kim et al. and Enomoto et al. characterize an interaction between DISC1 and girdin (also known as KIAA1212), and reveal how girdin, and the interaction between DISC1 and girdin, impact axon development, dendritic development, and the proper positioning of newborn neurons in the dentate gyrus. Girdin normally stimulates the function of AKT (Anai et al., 2005), and Kim et al. show that DISC1 binds to girdin and inhibits its function. Thus, the loss of DISC1 leaves girdin unopposed, resulting in excessive AKT signaling. Indeed, the developmental defects in neurons lacking DISC1 can be rescued by pharmacologically blocking the activation of an AKT downstream target. However, as shown by Enomoto et al., the loss of girdin produces deleterious effects on neuronal morphology, suggesting that a proper balance of girdin function is crucial.

Collectively, these studies thoroughly characterize the interaction between DISC1 and girdin, and shed much light on the consequences of this interaction on neuronal morphology as well as on the positioning of neurons in the dentate gyrus. The role of girdin in the pathology of neuropsychiatric diseases is unknown, and remains an interesting question for the future. Characterizing the molecules that act up- or downstream of DISC1 remains an important area of investigation and could aid the development of pharmacological interventions in the future. It’s intriguing that DISC1 acting through girdin regulates the activity of AKT as AKT1 was previously identified as a schizophrenia risk gene (Emamian et al., 2004). This suggests a convergence of multiple schizophrenia-associated genes in a shared pathway, and thus it will be important to determine if the DISC1-girdin-AKT1 pathway is particularly vulnerable in neuropsychiatric disorders.

References:

Blackwood DH, Fordyce A, Walker MT, St Clair DM, Porteous DJ, Muir WJ. Schizophrenia and affective disorders--cosegregation with a translocation at chromosome 1q42 that directly disrupts brain-expressed genes: clinical and P300 findings in a family. Am J Hum Genet . 2001 Aug 1 ; 69(2):428-33. Abstract

Millar JK, Christie S, Semple CA, Porteous DJ. Chromosomal location and genomic structure of the human translin-associated factor X gene (TRAX; TSNAX) revealed by intergenic splicing to DISC1, a gene disrupted by a translocation segregating with schizophrenia. Genomics . 2000 Jul 1 ; 67(1):69-77. Abstract

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

Kobayashi K. Targeting the hippocampal mossy fiber synapse for the treatment of psychiatric disorders. Mol Neurobiol . 2009 Feb 1 ; 39(1):24-36. Abstract

Anai M, Shojima N, Katagiri H, Ogihara T, Sakoda H, Onishi Y, Ono H, Fujishiro M, Fukushima Y, Horike N, Viana A, Kikuchi M, Noguchi N, Takahashi S, Takata K, Oka Y, Uchijima Y, Kurihara H, Asano T. A novel protein kinase B (PKB)/AKT-binding protein enhances PKB kinase activity and regulates DNA synthesis. J Biol Chem . 2005 May 6 ; 280(18):18525-35. Abstract

Emamian ES, Hall D, Birnbaum MJ, Karayiorgou M, Gogos JA. Convergent evidence for impaired AKT1-GSK3beta signaling in schizophrenia. Nat Genet . 2004 Feb 1 ; 36(2):131-7. Abstract

The paper by Singh and colleagues adds to the growing list of proteins that interact with DISC1 and deepens our understanding of the biochemical pathways through which DISC1 modulates various neurodevelopmental processes. They demonstrate that the Dixdc1 protein interacts biochemically with DISC1, and that it functions together with DISC1 in two separable processes: neuronal proliferation and migration.

Interestingly, the nature of the interaction between Dixdc1 and DISC1 differs in these two processes. Knockdown of either Dixdc1 or DISC1 reduces proliferation, but the effects of knocking both down together are additive, indicating the absence of any epistatic interaction. Moreover, the effects of knockdown of either gene alone can be rescued by overexpressing the other gene. This suggests a partial redundancy in their functions rather than an intimate relationship where they necessarily work together.

Knockdown of either gene also disrupts neuronal migration in the cortex, but in this case the defects cannot be rescued by overexpression of the other gene, suggesting...  Read more

The paper by Singh and colleagues adds to the growing list of proteins that interact with DISC1 and deepens our understanding of the biochemical pathways through which DISC1 modulates various neurodevelopmental processes. They demonstrate that the Dixdc1 protein interacts biochemically with DISC1, and that it functions together with DISC1 in two separable processes: neuronal proliferation and migration.

Interestingly, the nature of the interaction between Dixdc1 and DISC1 differs in these two processes. Knockdown of either Dixdc1 or DISC1 reduces proliferation, but the effects of knocking both down together are additive, indicating the absence of any epistatic interaction. Moreover, the effects of knockdown of either gene alone can be rescued by overexpressing the other gene. This suggests a partial redundancy in their functions rather than an intimate relationship where they necessarily work together.

Knockdown of either gene also disrupts neuronal migration in the cortex, but in this case the defects cannot be rescued by overexpression of the other gene, suggesting they may work more closely together in this context. These genes also act in distinct biochemical pathways in each context—through the Wnt/β-catenin pathway in proliferation and through a Cdk5-modulated Ndel1 pathway in cell migration, which impinges on the cytoskeleton.

These findings have several implications for the ongoing quest to understand the pathogenic mechanisms by which disruption of DISC1 pathways can result in psychiatric disease. First, as with PDE4B, NDE1, and PCM1, for example, they provide—through guilt by association—another viable candidate gene, Dixdc1, that may be analyzed for mutations in upcoming whole-genome sequencing efforts. More importantly, perhaps, they provide the means to dissociate the various functions of DISC1 during neurodevelopment.

One of the major difficulties in moving from gene identification to pathogenic mechanism has been that many of the genes with mutations linked to schizophrenia have highly pleiotropic effects; they play roles in many different processes, any one of which, or all of which together, might be responsible for the pathogenic effects. By dissecting the biochemical pathways mediating the different cellular functions of genes like DISC1, we can hope to develop animal models that can dissociate these functions and begin to dissect their contributions to pathogenesis.

The high prevalence of schizophrenia and related major mental illness, including bipolar disorder, in the Scottish family with the chromosome 1;11 translocation told us that the breakpoint gene DISC1 was an important key to unlocking the door on the molecular mechanisms underlying psychiatric illness (Millar et al., 2000; Blackwood et al., 2001). And so it has turned out to be (see review by Chubb et al., 2008). DISC1 is a scaffold protein that binds to and regulates other proteins critical in neurodevelopment and neurosignaling. We know the identity of several DISC1 interactors—PDE4, NDE1, NDEL1, PCM1, and Girdin amongst them—but at every turn, a new interactor seems to turn up.

Just last year, Li-Huei Tsai’s group identified GSK3β as a fascinating addition to the pantheon (Mao et al., 2009). GSK3β is interesting on two major counts: first, for its role in Wnt...  Read more

The high prevalence of schizophrenia and related major mental illness, including bipolar disorder, in the Scottish family with the chromosome 1;11 translocation told us that the breakpoint gene DISC1 was an important key to unlocking the door on the molecular mechanisms underlying psychiatric illness (Millar et al., 2000; Blackwood et al., 2001). And so it has turned out to be (see review by Chubb et al., 2008). DISC1 is a scaffold protein that binds to and regulates other proteins critical in neurodevelopment and neurosignaling. We know the identity of several DISC1 interactors—PDE4, NDE1, NDEL1, PCM1, and Girdin amongst them—but at every turn, a new interactor seems to turn up.

Just last year, Li-Huei Tsai’s group identified GSK3β as a fascinating addition to the pantheon (Mao et al., 2009). GSK3β is interesting on two major counts: first, for its role in Wnt signalling and neuronal transcription; second, as a target for the action of lithium, the front-line treatment for bipolar disorder. Now, her group reports on another novel DISC1 interactor, Dixdc1. I won’t attempt to summarize the whole story—see the SRF news story for more background and details and then seek out the original for the full story—but hers is a “must-read” study. The key points are that 1) Dixdc1 is a novel and potent DISC1 interactor; 2) Dixdc1, like DISC1, modulates GSK3β and Wnt signalling; 3) the Wnt pathway regulates neuronal progenitor proliferation; 4) the effects of DISC1 and Dixdc1 are additive and compensatory; 5) the same is true for their effect in neuronal migration, which occurs not through Wnt signaling, but rather through Cdk5-mediated, phosphorylation-dependent tripartite interaction with NDEL1.

This important new work highlights yet again the insights emerging from the DISC1 complex and its manifold consequences. It needs to be integrated with other recent important findings, including the link through Girdin to AKT signalling (Kim et al., 2009; Enomoto et al., 2009), which in turn links back to GSK3β and Wnt signaling. It also connects to other recent work suggesting a convergent link between DISC1 and a second, strong genetic candidate risk factor for major mental illness, NRG1, mediated via Erb2/3 and P13K/AKT (Seshadri et al., 2010) and to glutamatergic neurotransmission (Hayashi-Takagi et al., 2010).

It is worth reflecting whether or how these connections would have been made without the start point of DISC1 as an unambiguous causal link to psychiatric illness (Porteous, 2008). The new study raises important questions about the potential contribution to genetic risk from variation in each of these DISC1 pathway genes (Porteous, 2008; Hennah and Porteous, 2009). It begs the question of which proteins bind DISC1 in developmental time and cellular space and how this all affects neurodevelopment, neurosignaling, and brain circuitry (Porteous and Millar, 2009).

References:

Blackwood DH, Fordyce A, Walker MT, St. Clair DM, Porteous DJ, Muir WJ. Schizophrenia and affective disorders--cosegregation with a translocation at chromosome 1q42 that directly disrupts brain-expressed genes: clinical and P300 findings in a family. Am J Hum Genet. 2001;69:428-33. Abstract

Chubb JE, Bradshaw NJ, Soares DC, Porteous DJ, Millar JK. The DISC locus in psychiatric illness. Mol Psychiatry. 2008;13:36-64. Abstract

Enomoto A, Asai N, Namba T, Wang Y, Kato T, Tanaka M, Tatsumi H, Taya S, Tsuboi D, Kuroda K, Kaneko N, Sawamoto K, Miyamoto R, Jijiwa M, Murakumo Y, Sokabe M, Seki T, Kaibuchi K, Takahashi M. Roles of disrupted-in-schizophrenia 1-interacting protein girdin in postnatal development of the dentate gyrus. Neuron. 2009;63:774-87. Abstract

Hayashi-Takagi A, Takaki M, Graziane N, Seshadri S, Murdoch H, Dunlop AJ, Makino Y, Seshadri AJ, Ishizuka K, Srivastava DP, Xie Z, Baraban JM, Houslay MD, Tomoda T, Brandon NJ, Kamiya A, Yan Z, Penzes P, Sawa A. Disrupted-in-Schizophrenia 1 (DISC1) regulates spines of the glutamate synapse via Rac1. Nat Neurosci. 2010;13:327-32. Abstract

Hennah W, Porteous D. The DISC1 pathway modulates expression of neurodevelopmental, synaptogenic and sensory perception genes. PLoS One. 2009;4:e4906. Abstract

Kim JY, Duan X, Liu CY, Jang MH, Guo JU, Pow-anpongkul N, Kang E, Song H, Ming GL. DISC1 regulates new neuron development in the adult brain via modulation of AKT-mTOR signaling through KIAA1212. Neuron. 2009;63:761-73. Abstract

Mao Y, Ge X, Frank CL, Madison JM, Koehler AN, Doud MK, Tassa C, Berry EM, Soda T, Singh KK, Biechele T, Petryshen TL, Moon RT, Haggarty SJ, Tsai LH. Disrupted in schizophrenia 1 regulates neuronal progenitor proliferation via modulation of GSK3beta/beta-catenin signaling. Cell. 2009;136:1017-31. Abstract

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

Porteous D. Genetic causality in schizophrenia and bipolar disorder: out with the old and in with the new. Curr Opin Genet Dev. 2008;18:229-34. Abstract

Porteous D, Millar K. How DISC1 regulates postnatal brain development: girdin gets in on the AKT. Neuron. 2009;63:711-3. Abstract

Seshadri S, Kamiya A, Yokota Y, Prikulis I, Kano S, Hayashi-Takagi A, Stanco A, Eom TY, Rao S, Ishizuka K, Wong P, Korth C, Anton ES, Sawa A. Disrupted-in-Schizophrenia-1 expression is regulated by beta-site amyloid precursor protein cleaving enzyme-1-neuregulin cascade. Proc Natl Acad Sci U S A. 2010;107:5622-7. Abstract

Last year, an interesting paper (Mao et al., 2009) demonstrated that DISC1 regulates neurogenesis via directly interacting with and inhibiting GSK3, which subsequently activates the canonical Wnt pathway via stabilization of β-cantenin. Now a paper from the same group has identified a DISC1 binding protein named Dixdc1, which functions together with DISC1 to regulate neurogenesis and neuronal migration.

Specifically, the paper demonstrates that knocking down either DISC1 or Dixdc1 impairs neural progenitor proliferation and the activation of the canonical Wnt pathway, and double knocking down both proteins has an additive effect. In addition, the effects of knockdown of either gene alone can be fully rescued by overexpressing the other gene. These results suggest that DISC1 and Dixdc1 play redundant roles in regulation of neural progenitor cell proliferation via the GSK3-β-catenin pathway. However, disruption of the interaction between the two proteins also decreases the progenitor proliferation and the activation of...  Read more

Last year, an interesting paper (Mao et al., 2009) demonstrated that DISC1 regulates neurogenesis via directly interacting with and inhibiting GSK3, which subsequently activates the canonical Wnt pathway via stabilization of β-cantenin. Now a paper from the same group has identified a DISC1 binding protein named Dixdc1, which functions together with DISC1 to regulate neurogenesis and neuronal migration.

Specifically, the paper demonstrates that knocking down either DISC1 or Dixdc1 impairs neural progenitor proliferation and the activation of the canonical Wnt pathway, and double knocking down both proteins has an additive effect. In addition, the effects of knockdown of either gene alone can be fully rescued by overexpressing the other gene. These results suggest that DISC1 and Dixdc1 play redundant roles in regulation of neural progenitor cell proliferation via the GSK3-β-catenin pathway. However, disruption of the interaction between the two proteins also decreases the progenitor proliferation and the activation of the GSK3-β-catenin pathway, suggesting that they coordinate with each other. One potential explanation is that either DISC1 or Dixdc1 can function to inhibit GSK3 and activate the canonical Wnt pathway alone but at less efficiency. The formation of the protein complex may help better recruit GSK3 and thus increase the efficiency of GSK3 inhibition. The rescue results are probably due to overexpression of the proteins, which also increases the access to GSK3.

Very interestingly, the paper shows that knocking down either Dixdc1 or DISC1 also impairs neuronal migration. Unlike the effects in neurogenesis, those on neuronal migration cannot be rescued by overexpression of the other gene. In addition, activation of the canonical Wnt pathway via overexpression of a stabilized β-catenin cannot rescue the defect in neuronal migration. Thus, the authors suggest that DISC1 and Dixdc1 coordinate to regulate neuronal migration independent of the GSK3-β-catenin pathway, possibly via Ndel1, a protein known to regulate neuronal migration. As β-catenin is only one of the many substrates of GSK3 and many known substrates of GSK3 are cytoskeletal proteins (Zhou and Snider, 2005), it is possible that DISC1 and Dixdc1 coordinate to regulate neuronal migration via GSK3 signaling, which has recently been shown to regulate neuronal migration (Asada and Sanada, 2010). A unique feature of GSK3 signaling is the importance of its spatial regulation, which may explain the lack of rescuing effect with overexpression of one gene.

GSK3 signaling has recently been shown to play important roles in many neurodevelopmental processes, including neurogenesis, neuronal polarization, and axon outgrowth (Hur and Zhou, 2010). However, how GSK3 activity is regulated in the developing brain is not clear. This study not only identifies a potential regulator of GSK3, but also provides additional evidence that GSK3 signaling may be involved in neuronal migration.

References:

Asada, N., and Sanada, K. (2010). LKB1-mediated spatial control of GSK3beta and adenomatous polyposis coli contributes to centrosomal forward movement and neuronal migration in the developing neocortex. J Neurosci 30, 8852-8865. Abstract

Hur, E.M., and Zhou, F.Q. (2010). GSK3 signalling in neural development. Nat Rev Neurosci 11, 539-551. Abstract

Mao, Y., Ge, X., Frank, C.L., Madison, J.M., Koehler, A.N., Doud, M.K., Tassa, C., Berry, E.M., Soda, T., Singh, K.K., et al. (2009). Disrupted in schizophrenia 1 regulates neuronal progenitor proliferation via modulation of GSK3beta/beta-catenin signaling. Cell 136, 1017-1031. Abstract

Zhou, F.Q., and Snider, W.D. (2005). Cell biology. GSK-3beta and microtubule assembly in axons. Science 308, 211-214. Abstract