Signal transduction of clock genes in molecular clock

为了使许多蛋白质有效地发挥细胞功能，细胞事件必须在时间维度和空间维度上进行组织。组成细胞生物钟的细胞内分子振荡环协调各种具有基本或特定细胞功能的基因的表达时间。在哺乳动物中，在每个SCN神经元中产生的时钟基因表达的时间模式与其他细胞相结合并被放大，将其信号通过大脑传播，然后通过糖皮质激素和交感神经传播到周围器官。这些外周器官有自己的生物钟。在一些组织中，如肝脏，也有一个调节细胞周期的时钟，它与生物钟的组成和时间组织有强烈的相互作用。然而，一些组织，如睾丸，表达时钟基因，其功能，如果有的话，仍然不清楚。此外，在分化组织中，生物钟功能可能被暂停。因此，昼夜节律组织的突出可能并不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，那么研究快速复制和分化组织（如性腺）中的生物钟基因应该是一件有趣的事情。在睾丸中，肿瘤发生迅速，mPer1和Clock基因持续高表达。在小鼠胚胎的体体形成过程中，已知每2小时就有一对体体从体前中胚层萌发，这表明体体分裂是由一个2小时周期的生物钟控制的。新的bHLH Hes基因在体形成过程中周期性表达（每2小时）。体细胞时钟Hes7基因位于mPer1的下游。有趣的是，Hes6和mPer2基因也很接近，相距仅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，但在神经元成熟后表达微弱。相比之下，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素。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质增强子不当激活启动子的位置。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基因的印迹。如果在Per和Hes基因之间存在这样的基因组分离因子，可以想象，在发育中的组织中，“24小时慢”的生物钟被关闭，让“2小时快”的生物钟工作。形态发生后，涉及Hes基因的“2h快”生物钟被关闭，涉及mPer基因的“24h慢”生物钟被打开，以适应昼夜环境循环。这一方案可能适用于其他快速分化的组织，尽管Hes基因的表达动态在大多数器官中尚不清楚。分化组织中Per基因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不是必需的。同时，这也解释了为什么在没有生物钟的突变小鼠中胚胎发生似乎是完全正常的。少

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