| Research Abstract |
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
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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
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