PC12 cell model of inducible expression of mutant DISC1: new evidence for a dominant-negative mechanism of abnormal neuronal differentiation.
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.
Pletnikov
Mikhail V
MV
Division of Neurobiology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. mpletnik@jhmi.edu
Xu
Yanqun
Y
Ovanesov
Mikhail V
MV
Kamiya
Atsushi
A
Sawa
Akira
A
Ross
Christopher A
CA
D051701:Activating Transcription Factor 4 / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D005786:Gene Expression Regulation / Q000187:drug effects*; D018014:Gene Transfer Techniques; D006801:Humans; D009154:Mutation; D020932:Nerve Growth Factor / Q000494:pharmacology*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D016501:Neurites / Q000187:drug effects; D016716:PC12 Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D013997:Time Factors
C497110:Atf4 protein, rat; C412476:DISC1 protein, human; D009419:Nerve Tissue Proteins; C516550:Pafah1b1 protein, rat; D051701:Activating Transcription Factor 4; D020932:Nerve Growth Factor