DISC1 regulates neural progenitor proliferation via modulation of GSK3β/β-catenin signaling

By Yingwei Mao, Xuecai Ge, C. Frank, J. Madison, A. Koehler, M. Doud, C. Tassa, Erin M. Berry, T. Soda, Karun K. Singh and 5 more. 2009

818 citations recorded by the source corpus.

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.

Subfields: Cellular and Molecular Neuroscience, Molecular Biology

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Citations in the corpus

Adult Neurogenesis in the Mammalian Brain: Significant Answers and Significant Questions (2011, background): “…1 (DISC1; a gene implicated in major mental disorders) promotes proliferation of neural progenitors through the GSK3b/b-catenin pathway (Mao et al., 2009) while limiting dendritic growth and synapse formation of new neurons through AKT/mTOR signaling in the adult hippocampus (Duan et…”
Fragile X Mental Retardation Protein Regulates Proliferation and Differentiation of Adult Neural Stem/Progenitor Cells (2010, background): “Although one study suggests that Wnt signaling can also promote cell proliferation in the DG [56], other publications clearly point out the function of the Wnt signaling pathway in activating neuronal differentiation during adult neurogenesis, and inhibiting this pathway results in hippocampus-depen”
Adult Neurogenesis in the Hippocampus: From Stem Cells to Behavior. (2016, positive): “However, modulation of the pathway was achieved by injecting lentivirus-expressing shRNAs to suppress expression of Disrupted in Schizophrenia 1 (DISC1), which directly interacts with GSK3b, resulting in its inhibition and subsequent stabilization of b-Catenin (Mao et al., 2009).”
DISC1 regulates new neuron development in the adult brain via modulation of AKT-mTOR signaling through KIAA1212 (2009, neutral): “…et al., 2007; Li et al., 2007; Pletnikov et al., 2008; Shen et al., 2008), deletion of certain isoforms (Ishizuka et al., 2007; Koike et al., 2006; Kvajo et al., 2008), and lentivirus-mediated expression of short-hairpin RNA (shRNA) against Disc1 in the adult dentate gyrus (Mao et al., 2009).”
Emerging roles of Wnts in the adult nervous system (2010, background): “Further pointing to a role for GSK3β–β-catenin signalling in neurogenesis is the finding that suppression of expression of Disrupted in schizophrenia 1 ( DISC1 ), a protein encoded by a gene that is implicated in schizophrenia susceptibility and which directly interacts with GSK3β, decreased the pro”
Behavioural Brain Research (2016, neutral): “7 Indeed, neither group performed above chance during this Dark probe (both t 1) nor did the two groups differ from each other ( t 1) These results reveal that the rats had relied on visual cues to solve the task During dark trials”