Identifying circadian rhythm genes from mouse mutants

描述（由申请人提供）：在过去十年中，我们对哺乳动物生物钟分子机制的理解取得了巨大进展。昼夜节律振荡是由一组形成转录自动调节反馈环的基因产生的。在哺乳动物中，至少有七种不同的基因被认为是生物钟机制的“核心”昼夜节律元素。尽管取得了如此显著的进展，但很明显，哺乳动物中调节昼夜节律的大量基因仍有待发现和鉴定。正向遗传筛选是发现昼夜节律基因的最有效工具，我们在西北大学功能基因组学中心的神经基因组学项目中使用这种方法筛选小鼠基因组中的昼夜节律突变体。作为大规模ENU诱变筛选的一部分，鉴定了超过60种新的昼夜节律突变体，以创建神经系统和行为表型的突变小鼠资源。我们的具体目标是：1.目的：寻找小鼠昼夜节律周期“超时”突变的基因。我们将测试的假设，'加班'突变代表一种新的昼夜节律基因。2.确定在我们的大规模诱变筛选中分离的20个最稳健的昼夜节律突变体的遗传图谱位置。为了给昼夜节律研究提供一个更有价值的研究工具，我们建议绘制20个新的昼夜节律突变体。3.目的研究和鉴定一种新的小鼠夹带突变体--“摆动移位”突变体。我们将克隆的“摇摆移位”突变体和测试的假设，“摇摆移位”小鼠有一个分子或解剖学病变的光输入途径进入视交叉上核。这些新的昼夜节律突变体的特性和致病基因的鉴定，应该提供新的见解哺乳动物的昼夜节律钟的机制。

DESCRIPTION (provided by applicant): Over the past decade, tremendous progress has been made in our understanding of the molecular mechanism of circadian clocks in mammals. Circadian oscillations are generated by a set of genes that form a transcriptional autoregulatory feedback loop. In mammals, there are at least seven different genes that have been proposed as 'core' circadian elements of the clock mechanism. Despite this remarkable progress, it is clear that a significant number of genes that regulate circadian rhythms in mammals remain to be discovered and identified. Forward genetic screens have been the most effective tool for circadian gene discovery, and we have used this approach to screen the mouse genome for circadian rhythm mutants in the Neurogenomics Project in the Center for Functional Genomics at Northwestern University. Over 60 new circadian mutants were identified as part of a large-scale ENU mutagenesis screen to create a mutant mouse resource for nervous system and behavioral phenotypes. Our specific aims are: 1. To identify the gene responsible for the 'Overtime' circadian period mutant in mouse. We will test the hypothesis that the 'Overtime' mutant represents a novel circadian rhythm gene. 2. To determine the genetic map position of twenty of the most robust circadian mutants isolated in our large- scale mutagenesis screen. To provide a more valuable research tool for the circadian research community, we propose to map 20 new circadian mutants. 3. To characterize and identify the 'swing-shift' mutant which is a novel entrainment mutant in mice. We will clone the 'swing-shift' mutant and test the hypothesis that 'swing-shift' mice have either a molecular or an anatomical lesion in the photic input pathway into the suprachiasmatic nucleus. Characterization of these novel circadian mutants and the identification of the causative genes should provide new insight into the mechanism of the mammalian circadian clock.