Disrupted in Schizophrenia 1 Regulates Neuronal Progenitor Proliferation via Modulation of GSK3β/β-Catenin Signaling

Abstract

SUMMARY The Disrupted In Schizophrenia 1 (DISC1) gene is disrupted by a balanced chromosomal translocation (1; 11) (q42; q14.3) in a Scottish family with a high incidence of major depression, schizophrenia and bipolar disorder. Subsequent studies provided indications that DISC1 plays a role in brain development. Here we demonstrate that suppression of DISC1 expression reduces neural progenitor proliferation, leading to premature cell cycle exit and differentiation. Several lines of evidence suggest that DISC1 mediates this function by regulating GSK3β. First, DISC1 inhibits GSK3β activity through direct physical interaction, which reduces β-catenin phosphorylation and stabilizes β-catenin. Importantly, expression of stabilized β-catenin overrides the impairment of progenitor proliferation caused by DISC1 loss-of-function. Furthermore, GSK3 inhibitors normalize progenitor proliferation and behavioral defects caused by DISC1 loss-of-function. Together, these results implicate DISC1 in GSK3β/β-catenin signaling pathways and provide a framework for understanding how alterations in this pathway may contribute to the etiology of psychiatric disorders.

DRD2/AKT1interaction on D2 c-AMP independent signaling, attentional processing, and response to olanzapine treatment in schizophrenia

“…GSK-3β is an important molecular target downstream of AKT1 and is involved in a series on mechanisms of gene expression, including inactivation of β-catenin (26,42). Previous studies have indicated that AKT1 signaling inhibits GSK-3β activity via phosphorylation (43).…”

Disrupted in schizophrenia 1 (DISC1) is a constituent of the mammalian mitochondrial contact site and cristae organizing system (MICOS) complex, and is essential for oxidative phosphorylation

“…It has recently been demonstrated that MICOS-OPA1 synergy regulates the response to hypoxia by modulating cristae outlets and decreasing the number of ATP synthases dimers (50). Moreover, hDISC1 has been reported previously to inhibit glycogen synthase kinase 3b (GSK3b) (51), which in turn phosphorylates Drp1, increasing its GTPase activity and mitochondrial recruitment, with the resulting trigger of mitochondrial fragmentation (52). Whether DISC1 modulates mitochondrial dynamics through its function at MICOS or through its control on GSK3b-Drp1 will have to be explored in further investigations.…”

Dysregulation of neural calcium signaling in Alzheimer disease, bipolar disorder and schizophrenia

“…Such an interpretation is consistent with the fact that mutations in DISC1, which reduce its inhibitory effect on GSK-3β and is one of the prominent genes mutated in both schizophrenia and BD, results in a decrease in neurogenesis. 26 Single nucleotide polymorphisms (SNPs) of the Bcl-2 gene, which increase the risk of developing BD, are associated with elevated basal Ca 2+ levels and enhanced Ins(1,4,5)P 3 -mediated cytosolic Ca 2+ release. 27 Both Li + and valproate can markedly enhance the level of Bcl-2.…”