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The DISC1 Switch in Neurodevelopment

22 April 2011. Disrupted in schizophrenia 1 (DISC1), a major susceptibility factor for schizophrenia and other mental disorders, acts as a switch between neuronal proliferation and migration during brain development, according to a study appearing online April 6 in Nature. Led by Akira Sawa of Johns Hopkins University School of Medicine in Baltimore, Maryland, the study finds that the phosphorylation state of DISC1 flips the switch: when unphosphorylated at a certain site, DISC1 promotes neuron birth through Wnt signaling, and when phosphorylated, DISC1 aggregates with centrosomal proteins, which are instrumental for getting new neurons to move on to their proper locations in the brain.

The study unites previous findings of a role for DISC1 in both proliferation and migration. Reduced neuronal proliferation by neural progenitors has been reported in mice with a DISC1 mutation modeled after the translocation found in the Scottish family that originally led researchers to DISC1 (Shen et al., 2008), and DISC1 promotes new neuron birth through Wnt signaling—a pathway involved in the proliferation of a number of cell types (see SRF related news story). In addition, Sawa and his team have shown that DISC1 binds to Bardet-Biedel syndrome (BBS) proteins and recruits them to the centrosome, an event that readies new neurons for migration (see SRF related news story).

The new work illustrates how DISC1 can work through distinct pathways during the course of brain development. Combined with another study that explores the neuroanatomical consequences of point mutations to DISC1 from Albert Wong at the University of Toronto in Canada, these findings support the idea that DISC1 is critical for proper neurodevelopment, and that problems with the protein could leave a brain predisposed to mental illness.

Focus on phosphorylation
Suspecting that a phosphorylation-mediated modification could regulate whether DISC1 spurred proliferation or migration, first author Koko Ishizuka and colleagues began by simply asking whether human DISC1 protein could be phosphorylated. Indeed, it could, at three different sites, two of which were conserved in mouse DISC1: serine 170 (S170) and serine 58 (S58). Using site-directed mutagenesis, the researchers developed a "phospho-dead" version of the protein that was incapable of being phosphorylated at the S170 site, or a "phospho-mimic" that was constitutively phosphorylated at this site. They found that the phospho-dead DISC1 protein did not bind as well to BBS1 and BBS4 proteins as wild-type DISC1 did under conditions that safeguard phosphorylation. In contrast, the phospho-mimic DISC1 readily bound to BBS1, and in mouse cortical neurons, this resulted in correct localization of BBS1 to the centrosome. Mutations to the S58 site did not affect this interaction, suggesting that phosphorylation specifically at the S170 site is critical for migration.

On the other hand, DISC1 needed to be unphosphorylated at S170 to promote Wnt pathway signaling and spur cell proliferation. When DISC1 levels were knocked down in a non-neural cell line that reports Wnt pathway activity, the phospho-dead DISC1 could rescue Wnt signaling, but not the phospho-mimic DISC1 (as read out by β-catenin and cyclin D1 activity, downstream events in the Wnt pathway). An in vivo version of this experiment using in utero gene transfer in mice to introduce Wnt signaling constructs and RNAi to knock down endogenous DISC1 found the same requirement for unphosphorylated DISC1 to revive Wnt pathway activity in neurons.

Field test in the developing brain
These results suggest that, once phosphorylated at S170, DISC1 switches its role from proliferation to migration, and prompted the researchers to look for evidence of such a change in the developing mouse brain. Using an antibody that recognizes DISC1 only when it is phosphorylated at S170, they found higher antibody staining levels at E18, when migration is prominent, than at E14, when proliferation predominates. This staining was not found in the birthplace of new neurons, but rather in regions where only migrating neurons pass through.

Next, the researchers used co-immunoprecipitation to ask which proteins in mouse brain extracts normally bind to phosphorylated DISC1 at different time points in development. Between E14, when cell birth abounds, and E18, when migration is afoot, they found an increase in the amount of BBS1 protein bound by phosphorylated DISC1, and a similar sized decrease in the amount of bound glycogen synthase kinase 3β (GSK3β)—a key player in Wnt signaling. This same pattern emerged when progenitor cells and post-mitotic neurons were isolated from mouse brain, with post-mitotic neurons exhibiting increased levels of phosphorylated DISC1 at S170, increased BBS1 binding, and decreased affinity for GSK3β compared to progenitor cells.

Finally, when they knocked down DISC1 in embryos using in utero gene transfer, Ishizuka and colleagues could rescue proliferation at E13 by co-injecting phospho-dead or wild-type DISC1, whereas phospho-mimic DISC1 did not work. Conversely, co-injecting the phospho-mimic or wild-type DISC1 at E15 rescued migration, returning the number of migrating cells to normal, but the phospho-dead DISC1 did not. Based on their results, the authors propose that DISC1 unphosphorylated at S170 binds tightly to GSK3β to promote cell proliferation. Later in this model, when DISC1 is somehow phosphorylated at this site, DISC1 dissociates from GSK3β and shuttles BBS1 to the centrosome, triggering migration.

Point mutations point to neurodevelopment
This dual role for DISC1 is reinforced by Wong's study, appearing on March 2 in the Journal of Neuroscience, which explores how two missense point mutations—Q31L and L100P—of DISC1 in mice alter brain anatomy. Though not modeled after human disease-related variants, the two point mutations result in behaviors reminiscent of either depression or schizophrenia (see SRF related news story). In both mutant mouse lines, first author Frankie Lee and colleagues examined the cortex and found decreases in neuron number and neurogenesis—indicators of disturbed proliferation—as well as altered neuron distributions, suggesting that neurons were not migrating correctly compared to wild-type littermate controls. The neurons themselves had shorter dendrites and decreased spine densities than did neurons from wild-type mice, which suggest defects in connectivity. Despite the different behaviors in the two mouse lines, their neuroanatomical findings were largely similar and mimic some of the findings from postmortem brain tissue from individuals with schizophrenia, such as decreased neuron and spine densities.

Together, the new studies present a nuanced view of DISC1 function, with slight changes to DISC1, such as phosphorylation state having significant and widespread consequences in the brain. This calls for careful examination of even subtle modifications of DISC1—not just the major disruption that put it on the radar in the first place—to fully understand DISC1 function in health and in mental illness.—Michele Solis.

Ishizuka K, Kamiya A, Oh EC, Kanki H, Seshadri S, Robinson JF, Murdoch H, Dunlop AJ, Kubo KI, Furukori K, Huang B, Zeledon M, Hayashi-Takagi A, Okano H, Nakajima K, Houslay MD, Katsanis N, Sawa A. DISC1-dependent switch from progenitor proliferation to migration in the developing cortex. Nature. 2011 Apr 6. Abstract

Lee FH, Fadel MP, Preston-Maher K, Cordes SP, Clapcote SJ, Price DJ, Roder JC, Wong AH. Disc1 point mutations in mice affect development of the cerebral cortex. J Neurosci. 2011 Mar 2;31(9):3197-206. Abstract

Comments on News and Primary Papers
Primary Papers: Disc1 point mutations in mice affect development of the cerebral cortex.

Comment by:  Atsushi Kamiya
Submitted 2 May 2011 Posted 2 May 2011

In this paper, Lee et al. characterized DISC1 mutant mice,...  Read more

View all comments by Atsushi Kamiya

Comment by:  Albert H. C. Wong
Submitted 13 May 2011 Posted 13 May 2011

This recent and important paper by Sawa's group adds...  Read more

View all comments by Albert H. C. Wong
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