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.
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