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Signal transduction of clock genes in molecular clock

分子钟中时钟基因的信号转导

基本信息

批准号：
15200025
负责人：
OKAMURA Hitoshi
金额：
$ 30.53万
依托单位：
Kobe University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (A)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2004
项目状态：
已结题

项目摘要

Cellular events must be organized in the time dimension as well as in the space dimension for many proteins to perform their cellular functions effectively. The intracellular molecular oscillating loops that comprise the cell's circadian clock coordinate the timing of the expression of a variety of genes with basic or specific cellular functions. In mammals, the temporal pattern of clock gene expression generated in each SCN neuron is coupled to those of other cells and amplified, spreads its signals through the brain, and then, via glucocorticoids and sympathetic nerves, to peripheral organs. These peripheral organs have their own circadian clocks. In some tissues, such as liver, there is also a clock regulating cell cycle, which interacts strongly with the components and temporal organization of the circadian clock. Some tissues, however, such as testis, express clock genes whose function, if any, remains unclear. Furthermore, circadian clock function may be suspended in differentiat … More ing tissue. Thus, the prominence of circadian organization may not apply equally to all tissues under all conditions.If the cell cycle is intimately linked to the circadian clock, then it should be interesting to examine clock genes in rapidly replicating and differentiating tissues such as gonads. In testis where sper, matogeneis rapidly occurs, mPer1 and Clock genes are expressed constantly high. During somite genesis in mouse embryos, it is known that a pair of somites buds off from the presomitic mesoderm every 2 hours, suggesting that somite segmentation is controlled by a biological clock with a 2-hour cycle. The novel bHLH Hes genes show cyclic expression (every 2 hours) in the somite forming process. The somite clock Hes7 gene is located just downstream of mPer1. Interestingly, the Hes6 and mPer2 genes are also close to each other, only 2.8kbp apart. In the developing brain, it is known that neuronal stem cells express Hes1 and Hes6 genes abundantly in the proliferating and differentiating stages, but their expressions were faint after maturation of neurons. In contrast, Per1 and Per2 genes are expressed after completion of neurogenesis, and increased as their growth.One speculative explanation for such segregation of gene expression involves genome-segregating factors. In the study of the chicken β-globulin gene, insulator DNA elements were found to protect transcribed region from outside regulatory influences. They are present near chromatin domain boundaries or at sites where they prevent inappropriate activation of a promoter by a nearby heterogenous enhancer. In another example, the DNA-binding protein CTCF, which acts as a chromatin 'insulator, regulates imprinting of the mammalian Igf2 and H19 genes in a methylation-sensitive manner. If such genome segregating factors exist between the Per and Hes genes, one could imagine that the "24h-slow" circadian clock is switched off in developing tissue, allowing the "2h-rapid" clock to work. After morphogenesis, the "2h-rapid" clock involving Hes is switched off, and the "24h-slow" circadian clock involving mPer genes are switched on to adapt to the day-night environmental cycle. This scheme might apply to other rapidly differentiating tissues, although the expression dynamics of the Hes genes are not known for most organs. The silencing of Per genes in differentiating tissue could explain the enigma of why wee1 mediated G2 to M gating is not essential for coordinating cell division. Also, it would explain why embryogenesis seems to be perfectly normal in clock-less mutant mice. Less

细胞事件必须在时间维度和空间维度上组织，许多蛋白质才能有效地发挥其细胞功能。构成细胞生物钟的细胞内分子振荡环协调具有基本或特定细胞功能的多种基因的表达时间。在哺乳动物中，每个 SCN 神经元中产生的时钟基因表达的时间模式与其他细胞的时钟基因表达的时间模式耦合并放大，将其信号传播到大脑，然后通过糖皮质激素和交感神经传播到外周器官。这些外周器官有自己的生物钟。在某些组织中，例如肝脏，还存在调节细胞周期的时钟，它与生物钟的组成部分和时间组织强烈相互作用。然而，一些组织，例如睾丸，表达的时钟基因的功能（如果有的话）仍不清楚。此外，生物钟功能可能暂停在分化组织中。因此，昼夜节律组织的重要性可能并不同样适用于所有条件下的所有组织。如果细胞周期与生物钟密切相关，那么检查快速复制和分化的组织（如性腺）中的时钟基因应该很有趣。在精子快速发生的睾丸中，mPer1 和 Clock 基因持续高表达。在小鼠胚胎的体节发生过程中，每 2 小时就会有一对体节从前体中胚层中萌芽，这表明体节分割是由一个以 2 小时为周期的生物钟控制的。新型 bHLH Hes 基因在体节形成过程中显示出周期性表达（每 2 小时一次）。体节时钟 Hes7 基因位于 mPer1 的下游。有趣的是，Hes6 和 mPer2 基因也彼此接近，仅相距 2.8kbp。在发育中的大脑中，已知神经元干细胞在增殖和分化阶段大量表达Hes1和Hes6基因，但在神经元成熟后它们的表达微弱。相反，Per1和Per2基因在神经发生完成后表达，并随着它们的生长而增加。对这种基因表达分离的一种推测性解释涉及基因组分离因子。在鸡 β-球蛋白基因的研究中，发现绝缘子 DNA 元件可以保护转录区域免受外界调控的影响。它们存在于染色质结构域边界附近或防止附近异源增强子不适当激活启动子的位点。在另一个例子中，DNA结合蛋白CTCF作为染色质绝缘体，以甲基化敏感的方式调节哺乳动物Igf2和H19基因的印记。如果 Per 和 Hes 基因之间存在这样的基因组分离因子，人们可以想象发育中的组织中“24 小时慢”生物钟被关闭，从而允许“2 小时快”生物钟发挥作用。形态发生后，涉及Hes的“2小时快速”生物钟被关闭，涉及mPer基因的“24小时慢速”生物钟被打开以适应昼夜环境循环。尽管大多数器官的 Hes 基因的表达动态尚不清楚，但该方案可能适用于其他快速分化的组织。 Per 基因在分化组织中的沉默可以解释为什么 wee1 介导的 G2 到 M 门控对于协调细胞分裂并不重要。此外，它还可以解释为什么胚胎发生在无时钟突变小鼠中似乎完全正常。较少的