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Neurosci Res. 2007 Jul;58(3):234-44. Epub 2007 Mar 16.

PC12 cell model of inducible expression of mutant DISC1: new evidence for a dominant-negative mechanism of abnormal neuronal differentiation.

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  • 1Division of Neurobiology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. mpletnik@jhmi.edu

Abstract

A balanced chromosomal translocation, segregating with mental illnesses in a large Scottish family, interrupts the disrupted-in-schizophrenia 1 (DISC1) gene, which would result in loss of DISC1 function via haploinsufficiency or dominant-negative effects (or possibly could cause gain-of-function effects) if a truncated protein is present. To evaluate the effects of a predicted protein, mutant DISC1, we generated stable PC12 cell clones with inducible expression of mutant or full-length human DISC1 (hDISC1). Our study presents new observations that the inhibitory effects of mutant hDISC1 on NGF-induced neurite outgrowth are dependent on the level and timing of expression of mutant DISC1 and the concentrations of NGF, and are associated with altered sub-cellular distribution of endogenous DISC1 and ATF4, and decreased protein levels of LIS1. Thus, inducible expression of DISC1 in PC12 cell clones is a valuable in vitro model for further studying the molecular mechanisms likely due to loss of function of DISC1 relevant to the pathogenesis of major mental illnesses.

PMID:
17418909
[PubMed - indexed for MEDLINE]
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