Godinho Sofia I H, Maywood Elizabeth S, Shaw Linda, Tucci Valter, Barnard Alun R, Busino Luca, Pagano Michele, Kendall Rachel, Quwailid Mohamed M, Romero M Rosario, O'neill John, Chesham Johanna E, Brooker Debra, Lalanne Zuzanna, Hastings Michael H, Nolan Patrick M
Medical Research Council (MRC) Mammalian Genetics Unit, Harwell, Oxfordshire OX11 0RD, UK.
Science. 2007 May 11;316(5826):897-900. doi: 10.1126/science.1141138. Epub 2007 Apr 26.
By screening N-ethyl-N-nitrosourea-mutagenized animals for alterations in rhythms of wheel-running activity, we identified a mouse mutation, after hours (Afh). The mutation, a Cys(358)Ser substitution in Fbxl3, an F-box protein with leucine-rich repeats, results in long free-running rhythms of about 27 hours in homozygotes. Circadian transcriptional and translational oscillations are attenuated in Afh mice. The Afh allele significantly affected Per2 expression and delayed the rate of Cry protein degradation in Per2::Luciferase tissue slices. Our in vivo and in vitro studies reveal a central role for Fbxl3 in mammalian circadian timekeeping.
通过筛选经N-乙基-N-亚硝基脲诱变的动物的转轮活动节律变化，我们鉴定出一种小鼠突变体——“数小时后”（Afh）。该突变是Fbxl3（一种富含亮氨酸重复序列的F-盒蛋白）中的Cys(358)Ser替换，导致纯合子的自由运行节律延长至约27小时。Afh小鼠的昼夜节律转录和翻译振荡减弱。Afh等位基因显著影响Per2表达，并延缓了Per2::荧光素酶组织切片中Cry蛋白的降解速率。我们的体内和体外研究揭示了Fbxl3在哺乳动物昼夜节律计时中的核心作用。
