Pletnikov Mikhail V, Xu Yanqun, Ovanesov Mikhail V, Kamiya Atsushi, Sawa Akira, Ross Christopher A
Division of Neurobiology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
Neurosci Res. 2007 Jul;58(3):234-44. doi: 10.1016/j.neures.2007.03.003. Epub 2007 Mar 16.
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.
在一个苏格兰大家族中，一种与精神疾病共分离的平衡染色体易位中断了精神分裂症相关1（DISC1）基因。如果存在截短蛋白，这将通过单倍剂量不足或显性负效应导致DISC1功能丧失（或者可能导致功能获得效应）。为了评估预测蛋白突变型DISC1的作用，我们构建了可诱导表达突变型或全长人DISC1（hDISC1）的稳定PC12细胞克隆。我们的研究提出了新的观察结果，即突变型hDISC1对神经生长因子（NGF）诱导的神经突生长的抑制作用取决于突变型DISC1的表达水平和时间以及NGF的浓度，并且与内源性DISC1和活化转录因子4（ATF4）的亚细胞分布改变以及LIS1蛋白水平降低有关。因此，PC12细胞克隆中DISC1的可诱导表达是一种有价值的体外模型，可用于进一步研究可能由于DISC1功能丧失而与主要精神疾病发病机制相关的分子机制。
