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.
View all comments by Kevin J. Mitchell
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).
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
View all comments by David J. Porteous
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.
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
View all comments by Fengquan Zhou