Takumi T, Nagamine Y, Miyake S, Matsubara C, Taguchi K, Takekida S, Sakakida Y, Nishikawa K, Kishimoto T, Niwa S, Okumura K, Okamura H
Department of Anatomy and Brain Science, Kobe University School of Medicine, Kobe 650-0017, Japan; CREST, Japan Science and Technology Corporation, Japan.
Genes Cells. 1999 Jan;4(1):67-75. doi: 10.1046/j.1365-2443.1999.00238.x.
It is now becoming clear that the circadian rhythm of behaviours and hormones arises from a rhythm at the level of gene expression, and that mammals and Drosophila essentially use homologous genes as molecular gears in the control of circadian oscillation. In Drosophila, the period and timeless genes form a functional unit of the clock and its autoregulatory feedback loop for circadian rhythm. However, in mammals, the counterpart of timeless has not been found.
We have isolated a mammalian homologue of timeless, mTim, from the mouse brain. mTim is highly expressed, with a weak or absent rhythm in the suprachiasmatic nucleus, the mammalian circadian centre. In the retina, mTim mRNA was found to be expressed with a circadian rhythm, and a particularly robust cycle was observed in the presence of light/dark cycles. We demonstrated that mTIM physically associates with mPER1 in vitro and in the nuclei of cultured COS7 cells.
We have reported the isolation of the mouse timeless cDNA, the expression of the mTim mRNA and an interaction of mTIM with mPER1. These results indicate that the autoregulatory feedback mechanism of circadian oscillation of the period gene may also be conserved in mammals.
现在越来越清楚的是，行为和激素的昼夜节律源于基因表达水平的节律，并且哺乳动物和果蝇在控制昼夜节律振荡时基本上使用同源基因作为分子齿轮。在果蝇中，周期基因和无时间基因形成了生物钟及其昼夜节律自动调节反馈环的功能单元。然而，在哺乳动物中，尚未发现无时间基因的对应物。
我们从小鼠大脑中分离出了无时间基因的哺乳动物同源物mTim。mTim在视交叉上核（哺乳动物昼夜节律中心）中高度表达，节律微弱或无节律。在视网膜中，发现mTim mRNA以昼夜节律表达，并且在明暗周期存在的情况下观察到特别强烈的周期。我们证明，mTIM在体外和培养的COS7细胞核中与mPER1发生物理结合。
我们报道了小鼠无时间基因cDNA的分离、mTim mRNA的表达以及mTIM与mPER1的相互作用。这些结果表明，周期基因昼夜节律振荡的自动调节反馈机制在哺乳动物中可能也是保守的。
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