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

Neurosci Res. 2007 Jul;58(3):234-44. doi: 10.1016/j.neures.2007.03.003. Epub 2007 Mar 16.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activating Transcription Factor 4 / metabolism
  • Analysis of Variance
  • Animals
  • Cell Differentiation / drug effects
  • Cell Differentiation / physiology*
  • Gene Expression Regulation / drug effects*
  • Gene Transfer Techniques
  • Humans
  • Mutation*
  • Nerve Growth Factor / pharmacology*
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Neurites / drug effects
  • PC12 Cells / cytology
  • PC12 Cells / drug effects*
  • PC12 Cells / metabolism
  • Rats
  • Time Factors

Substances

  • Atf4 protein, rat
  • DISC1 protein, human
  • Nerve Tissue Proteins
  • Pafah1b1 protein, rat
  • Activating Transcription Factor 4
  • Nerve Growth Factor