TY - JOUR
T1 - PC12 cell model of inducible expression of mutant DISC1
T2 - New evidence for a dominant-negative mechanism of abnormal neuronal differentiation
AU - Pletnikov, Mikhail V.
AU - Xu, Yanqun
AU - Ovanesov, Mikhail V.
AU - Kamiya, Atsushi
AU - Sawa, Akira
AU - Ross, Christopher A.
N1 - Funding Information:
We appreciate the support of Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine. This work was supported by the grants from the Stanley Medical Research Institute and National Alliance for Research on Schizophrenia and Depression.
Copyright:
Copyright 2009 Elsevier B.V., All rights reserved.
PY - 2007/7
Y1 - 2007/7
N2 - 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.
AB - 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.
KW - ATF4
KW - DISC1
KW - LIS1
KW - PC12 cells
KW - Schizophrenia
UR - http://www.scopus.com/inward/record.url?scp=34447287515&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=34447287515&partnerID=8YFLogxK
U2 - 10.1016/j.neures.2007.03.003
DO - 10.1016/j.neures.2007.03.003
M3 - Article
C2 - 17418909
AN - SCOPUS:34447287515
SN - 0168-0102
VL - 58
SP - 234
EP - 244
JO - Neuroscience Research
JF - Neuroscience Research
IS - 3
ER -