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DISC1: A Matter of Life or Death for Neural Progenitors

19 March 2009. The disrupted in schizophrenia 1 (DISC1) gene plays a central role in the production of new neurons during brain development and into adulthood, says the cover story in tomorrow’s issue of Cell. The study, from Li-Huei Tsai and colleagues at MIT and Harvard, shows that DISC1 regulates the Wnt pathway, which controls the activity of the glycogen synthase kinase 3β (GSK3β) and proliferation of neural progenitor cells. The data suggest that disruption of neurogenesis in the adult brain can account for some of the behavioral effects of DISC1 disruption, and offers up GSK3β as a potential therapeutic target for schizophrenia and depression. (Also see editorial in the same issue by Guo-li Ming and Hongjun Song of Johns Hopkins University.)

The DISC1 gene was first discovered as the casualty of a chromosomal translocation in a large Scottish family with a high incidence of schizophrenia, bipolar disorder, and major depression. As much as catastrophic genetic mistakes like the DISC1 translocation offer researchers a window into disease pathophysiology, it can be challenging to get a clear picture of mechanism. Work over the past decade has linked DISC1 mutations to aberrant neuronal development (see Kamiya et al., 2005 and SRF related news story), and the protein also appears to play a role in adult neurogenesis and differentiation (see SRF related news story). The Disc1 protein takes part in the functions of mature neurons as well, and how these different facets of its physiology contribute to psychiatric disease remains unclear.

DISC1 in embryonic progenitor cells
In the new study, first author Yingwei Mao and coworkers use DISC1 knockdown and overexpression in mice to build the case that the protein is critical for the proliferation of progenitor cells. In the fetal mouse brain, they find that expression of DISC1 peaks at the height of neurogenesis at embryonic days 14-15 and in adult brain regions associated with active neuron production. When the researchers suppressed DISC1 expression using siRNA either in progenitor cells in culture or in vivo, they found a decrease in cell proliferation. In vivo, the delivery of DISC1 siRNA by electroporation into embryonic brain resulted in a loss of proliferative cells, premature differentiation and an overall reduction of the progenitor pool.

Mao and colleagues go on to show that DISC1 regulates proliferation through the Wnt pathway, in which GSK3β controls levels of the transcriptional activator β-catenin and keeps the cells cycling. DISC1 directly interacts with and inhibits GSK3β, the researchers show, which keeps β-catenin levels high and promotes cell proliferation. Knockdown of DISC1 using siRNA resulted in the activation of GSK3β, a loss of β-catenin, inhibition of β-catenin-regulated gene expression, the exit of progenitors from the cell cycle, and early differentiation.

If the downstream effects of DISC1 deficiency rely on activation of GSK3β and loss of β-catenin, then inhibition of GSK3β might overcome the loss of DISC1. Consistent with this idea, the researchers found that two different GSK3β inhibitors restored proliferation to DISC1-minus embryonic progenitor cells in vitro and in vivo. Boosting GSK3β by overexpression in embryonic brain reduced the number of dividing progenitors, and this effect was overcome by co-expressing DISC1. The results all support the idea that DISC1 regulates progenitor number through inhibition of GSK3β, and provide a possible developmental pathway to explain schizophrenia risk.

DISC1 in the adult hippocampus
DISC1 had effects on progenitor cells in adult brain, too. Injection of DISC1 siRNA into the dentate gyrus of the hippocampus decreased the proliferation of adult progenitor cells. The loss of progenitors had behavioral consequences: the siRNA-treated mice showed hyperactivity in response to novel environment, a model for positive symptoms of schizophrenia. The mice also displayed depression-related behaviors (less effort in a forced swim test) but not increased anxiety. The behavioral changes were all normalized by treatment with the GSK3β inhibitor SB-216763, which restored normal progenitor proliferation. “These results not only link DISC1-regulated adult neurogenesis with behavioral outputs, but also underscore a critical role for DISC1 in fine-tuning GSK3β-mediated signaling events,” the authors write. In this regard, they note that DISC1 function resembles that of lithium chloride, a long-used medication for bipolar disorder that directly and indirectly inhibits GSK3β activity (see SRF related news story).

This is not the first time that GSK3β has been implicated in schizophrenia or behavior (see SRF related news story). The kinase sits downstream of the dopamine D2 receptor, the target for antipsychotic drugs. The schizophrenia risk genes neuregulin-1 and Akt (the latter activated by D2 signaling, in fact) both regulate GSK3β. Likewise, defects in neurogenesis have been implicated in schizophrenia and in depression. The new findings that DISC1 occupies a critical regulatory position in neurogenesis pulls together a lot of these previous observations and makes a strong argument for GSK3β as a potential target for new therapies.—Pat McCaffrey.

Reference:
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 L-H. Disrupted in schizophrenia 1 regulates neuronal progenitor proliferation via modulation of GSK3beta/beta-catenin signaling. Cell. 20 March 2009; (136):1017-1031. Abstract

Ming GL, Song H. DISC1 partners with GSK3beta in neurogenesis. Cell. 2009 Mar 20 ; 136(6):990-2. Abstract

 
Comments on News and Primary Papers
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...  Read more


View all comments by Khaled Rahman

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...  Read more


View all comments by Simon Lovestone

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...  Read more


View all comments by Nick Brandon

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...  Read more


View all comments by Akira Sawa
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