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以及空间维度中进行组织，以使许多蛋白质有效地执行其细胞功能。细胞内分子振荡环组成，该环由细胞的昼夜节律坐在各种基因表达的时机，具有基本或特定的细胞功能。在哺乳动物中，在每个SCN神经元中产生的时钟基因表达的暂时模式与其他细胞的偶联并扩展，并通过大脑传播其信号，然后通过糖皮质激素和交感神经，以及周围的器官。这些外围器官有自己的昼夜节律。在某些组织（例如肝脏）中，还有一个时钟调节细胞周期，该周期与昼夜节律时钟的成分和临时组织强烈相互作用。然而，某些组织（例如睾丸）明确的时钟基因，其功能（如果有）仍然不清楚。时钟功能可能会悬浮在不同的组织中。这是昼夜节律组织在所有条件下的所有组织的突出。如果细胞周期与昼夜节律时钟密切相关，那么在快速复制和区分性组织（例如性腺）中考试时钟基因应该很有趣。在睾丸中，SPER，迅速发生结构，MPER1和时钟基因不断表达。在小鼠胚胎中的躯干起源期间，众所周知，每2小时从前中胚层从前中胚层散发出一对固体，这表明Somite分割受2小时循环的生物钟控制。新型的BHLH HES基因在体系形成过程中显示出环状表达（每2小时）。 Somite Clock Hes7基因位于MPER1的下游。有趣的是，HES6和MPER2基因也彼此接近，只有2.8kbp。在发育中的大脑中，众所周知，神经元干细胞在增殖和分化阶段中表达HES1和HES6基因，但它们的表达在神经元成熟后微弱。相反，神经发生后表达了PER1和PER2基因，并随着其生长而增加。这种基因表达分离的投机解释涉及基因组分离的因子。在对鸡β-球蛋白基因的研究中，发现绝缘子DNA元素可保护转录区域免受外部调节影响。它们存在于染色质结构域的边界附近，或者在阻止附近异质增强子对启动子不适当激活的位置。在另一个示例中，充当染色质的绝缘子的DNA结合蛋白CTCF以甲基化敏感的方式调节哺乳动物IGF2和H19基因的印记。这种基因组分离因子存在于PER和HES基因之间，人们可以想象“ 24h-Slow”昼夜节律时钟在发育的组织中被关闭，从而使“ 2H-Rapid”的时钟起作用。形态发生后，涉及HES的“ 2H-Rapid”时钟被关闭，并且涉及MPER基因的“ 24h-Slow”昼夜节律被打开以适应日夜的环境周期。尽管HES基因的表达动力学在大多数器官中都不知道，但该方案可能适用于其他快速区分的时机。分化组织中的每个基因的沉默可以解释为什么WEE1介导的G2介导的g2析出的谜团对于协调的细胞分裂不是必不可少的。同样，它可以解释为什么在无钟突变小鼠中胚胎发生似乎完全正常。较少的