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PMID:19303846

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Citation

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 and Tsai, LH (2009) Disrupted in schizophrenia 1 regulates neuronal progenitor proliferation via modulation of GSK3beta/beta-catenin signaling. Cell 136:1017-31

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 GSK3beta. First, DISC1 inhibits GSK3beta activity through direct physical interaction, which reduces beta-catenin phosphorylation and stabilizes beta-catenin. Importantly, expression of stabilized beta-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 GSK3beta/beta-catenin signaling pathways and provide a framework for understanding how alterations in this pathway may contribute to the etiology of psychiatric disorders.

Links

PubMed PMC2704382 Online version:10.1016/j.cell.2008.12.044

Keywords

Adult Stem Cells/cytology; Adult Stem Cells/metabolism; Animals; Brain/cytology; Brain/embryology; Embryo, Mammalian/metabolism; Gene Knockdown Techniques; Glycogen Synthase Kinase 3/metabolism; Humans; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Nerve Tissue Proteins/metabolism; Neurogenesis; Neurons/cytology; Neurons/metabolism; Signal Transduction; Stem Cells/cytology; Stem Cells/metabolism; beta Catenin/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:AXIN1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P49841

F

Seeded From UniProt

complete

HUMAN:CTNB1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P49841

F

Seeded From UniProt

complete

HUMAN:GSK3B

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:O15169

F

Seeded From UniProt

complete

HUMAN:GSK3B

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P35222

F

Seeded From UniProt

complete

HUMAN:GSK3B

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q811T9

F

Seeded From UniProt

complete

MOUSE:DISC1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q9WV60

F

Seeded From UniProt

complete

MOUSE:DISC1

involved_in

GO:0030177: positive regulation of Wnt signaling pathway

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:DISC1

involved_in

GO:0002052: positive regulation of neuroblast proliferation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:DISC1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P49841

F

Seeded From UniProt

complete

MOUSE:GSK3B

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q811T9

F

Seeded From UniProt

complete

HUMAN:DISC1

involved_in

GO:0030177: positive regulation of Wnt signaling pathway

ECO:0000316: genetic interaction evidence used in manual assertion

P

Seeded From UniProt

Missing: with/from

HUMAN:DISC1

involved_in

GO:0002052: positive regulation of neuroblast proliferation

ECO:0000316: genetic interaction evidence used in manual assertion

P

Seeded From UniProt

Missing: with/from


See also

References

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