However, most of these results have proved difficult to reproduce, with the notable exception of DISC1 modulation of GSK-3β (reviewed in Hur and Zhou, 2010 and Inestrosa and Arenas, 2010). The present

study by Tsai and colleagues (Singh et al., 2011) posed check details the following questions: Do genetic changes in DISC1 that have been linked to schizophrenia alter canonical Wnt signaling? And if so, how do they affect neuronal development? They addressed these questions by using a highly innovative combination of in vivo and in vitro model systems that span three species (mouse, zebrafish, and human). Their novel experimental approach began by resequencing the exomes of over 700 schizophrenic, bipolar, or control patients. This allowed them to derive a set of common and rare DISC1 variants to explore further. Then they focused on validating the functionality of individual nonsynonymous (i.e., protein-altering) SNPs. Each

of these SNPs causes single amino acid changes to DISC1 and include the common missense variants R264Q, L607F, and S704C, as well as the rare variant A83V (reviewed in Chubb et al., 2008). By using a standard assay of canonical Wnt signaling, they demonstrated that wild-type DISC1 potentiates canonical Wnt signaling in human and mouse cell SB431542 lines. However, this potentiation was abrogated by amino acid substitutions near the GSK-3β binding site, but not by a more distal substitution. In sum, these SNPs reduced canonical Wnt signaling by altering DISC1′s interaction with GSK-3β.

When tested in mice, the SNPs that reduce canonical activity produced a commensurate decrease in neural progenitor cell proliferation and an increase in neuronal fate commitment. This is consistent with studies demonstrating that human neural progenitors require baseline canonical Wnt activity to remain proliferative Lenvatinib clinical trial and undifferentiated (Wexler et al., 2009). Another innovative aspect of this study was the authors’ ability to validate their findings using human lymphoblast cells lines, derived from patients harboring each of the common SNPs. Specifically, they showed that Wnt stimulation produced less activation of the canonical pathways in lymphoblasts homozygous for the 264QQ polymorphisms, compared to those wild-type cells (i.e., RR264). They also found that Wnt-stimulated signaling was significantly lower in lymphoblasts from bipolar patients, compared to controls. This further supports the hypothesis that lithium’s efficacy in treating bipolar disorder stems from its ability to restore adequate Wnt signaling in affected individuals, given that lithium mimics canonical signaling, including in neural adult progenitors (Wexler et al., 2008). Although these data are intriguing, they must be interpreted cautiously, because lymphoblasts can only partially recapitulate the behavior of neurons.