Desbonnet Lieve, Cox Rachel, Tighe Orna, Lai Donna, Harvey Richard P, Waddington John L, O'Tuathaigh Colm M P
Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin 2, Ireland; School of Life Sciences, West Medical Building, University of Glasgow, Glasgow, UK.
Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin 2, Ireland.
Behav Brain Res. 2017 Mar 1;320:113-118. doi: 10.1016/j.bbr.2016.11.049. Epub 2016 Dec 1.
The complex genetic origins of many human disorders suggest that epistatic (gene×gene) interactions may contribute to a significant proportion of their heritability estimates and phenotypic heterogeneity. Simultaneous disruption of the developmental genes and schizophrenia risk factors Neuregulin-1 (NRG1) and Disrupted-in-schizophrenia 1 (DISC1) in mice has been shown to produce disease-relevant and domain-specific phenotypic profiles different from that observed following disruption of either gene alone. In the current study, anxiety and stress responsivity phenotypes in male and female mutant mice with simultaneous disruption of DISC1 and NRG1 were examined. NRG1×DISC1 mutant mice were generated and adult mice from each genotype were assessed for pain sensitivity (hot plate and tail flick tests), anxiety (light-dark box), and stress-induced hypothermia. Serum samples were assayed to measure circulating levels of pro-inflammatory cytokines. Mice with the NRG1 mutation, irrespective of DISC1 mutation, spent significantly more time in the light chamber, displayed increased core body temperature following acute stress, and decreased pain sensitivity. Basal serum levels of cytokines IL8, IL1β and IL10 were decreased in NRG1 mutants. Mutation of DISC1, in the absence of epistatic interaction with NRG1, was associated with increased serum levels of IL1β. Epistatic effects were evident for IL6, IL12 and TNFα. NRG1 mutation alters stress and pain responsivity, anxiety, and is associated with changes in basal cytokine levels. Epistasis resulting from synergistic NRG1 and DISC1 gene mutations altered pro-inflammatory cytokine levels relative to the effects of each of these genes individually, highlighting the importance of epistatic mechanisms in immune-related pathology.
许多人类疾病复杂的遗传起源表明，上位性（基因×基因）相互作用可能在很大比例的遗传度估计和表型异质性中起作用。在小鼠中同时破坏发育基因和精神分裂症风险因子神经调节蛋白-1（NRG1）及精神分裂症相关破坏基因1（DISC1），已显示会产生与疾病相关的、特定领域的表型特征，这与单独破坏任一基因时观察到的情况不同。在当前研究中，对同时破坏DISC1和NRG1的雄性和雌性突变小鼠的焦虑和应激反应表型进行了检查。生成了NRG1×DISC1突变小鼠，并对每种基因型的成年小鼠进行了疼痛敏感性（热板和甩尾试验）、焦虑（明暗箱试验）和应激诱导体温过低的评估。检测血清样本以测量促炎细胞因子的循环水平。无论DISC1是否突变，具有NRG1突变的小鼠在明室中停留的时间显著更长，在急性应激后体温升高，疼痛敏感性降低。NRG1突变小鼠中细胞因子IL8、IL1β和IL10的基础血清水平降低。在没有与NRG1上位性相互作用的情况下，DISC1突变与IL1β血清水平升高有关。IL6、IL12和TNFα存在上位性效应。NRG1突变会改变应激和疼痛反应、焦虑，并与基础细胞因子水平的变化有关。NRG1和DISC1基因突变协同产生的上位性效应相对于这些基因各自单独的效应改变了促炎细胞因子水平，突出了上位性机制在免疫相关病理学中的重要性。
