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

Mikhail V. Pletnikov, Yanqun Xu, Mikhail V. Ovanesov, Atsushi Kamiya, Akira Sawa, Christopher A. Ross

Research output: Contribution to journalArticlepeer-review

29 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)234-244
Number of pages11
JournalNeuroscience Research
Volume58
Issue number3
DOIs
StatePublished - Jul 2007

Keywords

  • ATF4
  • DISC1
  • LIS1
  • PC12 cells
  • Schizophrenia

ASJC Scopus subject areas

  • General Neuroscience

Fingerprint

Dive into the research topics of 'PC12 cell model of inducible expression of mutant DISC1: New evidence for a dominant-negative mechanism of abnormal neuronal differentiation'. Together they form a unique fingerprint.

Cite this