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

Yingwei Mao, Xuecai Ge, Christopher L. Frank, Jon M. Madison, Angela N. Koehler, Mary Kathryn Doud, Carlos Tassa, Erin M. Berry, Takahiro Soda, Karun K. Singh, Travis Biechele, Tracey L. Petryshen, Randall T. Moon, Stephen J. Haggarty, Li Huei Tsai

Research output: Contribution to journalArticle

560 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1017-1031
Number of pages15
JournalCell
Volume136
Issue number6
DOIs
StatePublished - Mar 20 2009

Fingerprint

Catenins
Schizophrenia
Modulation
Phosphorylation
Brain
Genes
Cells
Defects
Genetic Translocation
Bipolar Disorder
Psychiatry
Cell Differentiation
Cell Cycle
Depression

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Mao, Y., Ge, X., Frank, C. L., Madison, J. M., Koehler, A. N., Doud, M. K., ... Tsai, L. H. (2009). Disrupted in Schizophrenia 1 Regulates Neuronal Progenitor Proliferation via Modulation of GSK3β/β-Catenin Signaling. Cell, 136(6), 1017-1031. https://doi.org/10.1016/j.cell.2008.12.044
Mao, Yingwei ; Ge, Xuecai ; Frank, Christopher L. ; Madison, Jon M. ; Koehler, Angela N. ; Doud, Mary Kathryn ; Tassa, Carlos ; Berry, Erin M. ; Soda, Takahiro ; Singh, Karun K. ; Biechele, Travis ; Petryshen, Tracey L. ; Moon, Randall T. ; Haggarty, Stephen J. ; Tsai, Li Huei. / Disrupted in Schizophrenia 1 Regulates Neuronal Progenitor Proliferation via Modulation of GSK3β/β-Catenin Signaling. In: Cell. 2009 ; Vol. 136, No. 6. pp. 1017-1031.
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abstract = "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.",
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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, LH 2009, 'Disrupted in Schizophrenia 1 Regulates Neuronal Progenitor Proliferation via Modulation of GSK3β/β-Catenin Signaling', Cell, vol. 136, no. 6, pp. 1017-1031. https://doi.org/10.1016/j.cell.2008.12.044

Disrupted in Schizophrenia 1 Regulates Neuronal Progenitor Proliferation via Modulation of GSK3β/β-Catenin Signaling. / Mao, Yingwei; Ge, Xuecai; Frank, Christopher L.; Madison, Jon M.; Koehler, Angela N.; Doud, Mary Kathryn; Tassa, Carlos; Berry, Erin M.; Soda, Takahiro; Singh, Karun K.; Biechele, Travis; Petryshen, Tracey L.; Moon, Randall T.; Haggarty, Stephen J.; Tsai, Li Huei.

In: Cell, Vol. 136, No. 6, 20.03.2009, p. 1017-1031.

Research output: Contribution to journalArticle

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T1 - Disrupted in Schizophrenia 1 Regulates Neuronal Progenitor Proliferation via Modulation of GSK3β/β-Catenin Signaling

AU - Mao, Yingwei

AU - Ge, Xuecai

AU - Frank, Christopher L.

AU - Madison, Jon M.

AU - Koehler, Angela N.

AU - Doud, Mary Kathryn

AU - Tassa, Carlos

AU - Berry, Erin M.

AU - Soda, Takahiro

AU - Singh, Karun K.

AU - Biechele, Travis

AU - Petryshen, Tracey L.

AU - Moon, Randall T.

AU - Haggarty, Stephen J.

AU - Tsai, Li Huei

PY - 2009/3/20

Y1 - 2009/3/20

N2 - 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.

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