CHEMICAL MUTAGENESIS IN MOUSE CIRCADIAN RHYTHMS

从原核生物到哺乳动物，几乎所有的生物都存在由内源性生物钟驱动的昼夜节律，在恒定的条件下，昼夜节律的周期约为24小时。昼夜节律的特征是所有物种共有的，但昼夜节律的分子机制尚不清楚。本研究的目的是分离小鼠的昼夜节律突变体，以了解昼夜节律的分子机制。为此，我们使用了三种不同的策略。一种是化学诱变，另一种是从野生小鼠群体中分离突变体，第三种是近交系的筛选。使用这种策略，我们已经发现了几个突变小鼠表现出异常的节奏。此外，我们在饲养小鼠的过程中意外地发现了另一种突变。野生小鼠群体中发现的突变的特征是恒定条件下的昼夜节律丧失和昼夜周期缩短。遗传分析表明，心律失常性状是隐性的， ...更多信息 突变体与C57 BL/6 J小鼠的F1代表现出正常的节律，F2代和回交后代表现出分离。在近交系的筛选中，发现CS小鼠具有异常的昼夜节律特性，包括较长的自由奔跑时间，大的活动相，在恒定黑暗中的自由奔跑节律分裂。为了对影响自由奔跑时间的基因进行染色体定位，采用QTL（Quantitative trait locus）定位方法对CS小鼠与C57 BL/6 J小鼠杂交F2代进行了分析。结果，检测到4号染色体（LOD评分=3.5）、12号染色体（LOD评分=3.4）和19号染色体（LOD评分=3.7）上的三个临时区域。在与MSM小鼠的另一个杂交中研究了这些潜在的QTL，发现在19号染色体上检测到LOD评分为4.2的相同区域。这些结果表明，CS小鼠的自由奔跑时间受多个基因的影响，特别是19号染色体上的QTL强烈影响该时间。在小鼠杂交过程中发现的最后一个突变的特征是在恒定的黑暗下突然紊乱的节奏，有时是8小时的周期性。对于未来的研究，这种突变小鼠保持适当的育种方法。少

Circadian rhythms which are driven by endogenous clocks with a period of approximately 24 hr under constant condition are observed in almost all creatures from procaryotes to mammals. The features of circadian rhythms are common to all species, but molecular mechanisms of circadian rhythms are unclear. The purpose of this study is to isolate circadian mutant in mice to understand molecular mechanisms of circadian rhythms. For this, we have used 3 different strategies. One is chemical mutagenesis, another is isolating a mutant from wild mice population and a third is a screening of inbred strains. Using this strategies, we have found several mutant mice which show abnormal rhythmicity. Furthermore, we have accidentally found another mutation in the course of breeding mice. The mutation found in wild mice population is characterized by loss of circadian rhythms under constant condition and shorter circadian period. Genetic analysis indicated that the arrythmic trait is recessive because … More F1 mice between the mutant and C57BL/6J show normal rhythms and the phenotype segregates in F2 and backcross. In the screening of inbred lines, CS mice were found to have abnormal circadian properties including longer free-running period, large activity phase, splitting of free-running rhythms in constant darkness. In order to identify chromosomal location of the genes influencing free-running period, we analyzed F2 progeny from the cross between CS and C57BL/6J mice by QTL (Quantitative trait locus) mapping method. As a result, three provisional regions on chromosomes 4 (LOD score=3.5), 12 (LOD score=3.4) and 19 (LOD score=3.7) were detected. These potential QTLs are investigated in another cross with MSM mice and it was found that the same region on chromosome 19 is detected with LOD score 4.2. These results suggest that the free-running period of CS mice is affected by multiple genes and particularly the QTL on chromosome 19 strongly affect the period. The last mutation found during the crossing of mice is characterized by suddenly disorganized rhythm and sometimes 8 hr periodicity under constant darkness. For future studies, this mutant mice were maintained with an appropriate breeding method. Less