| Project/Area Number |
15209012
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| Research Category |
Grant-in-Aid for Scientific Research (A)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
General medical chemistry
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| Research Institution | Kyoto University |
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Principal Investigator |
KAGEYAMA Ryoichiro Kyoto University, Institute for Virus Research, Professor, ウイルス研究所, 教授 (80224369)
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| Co-Investigator(Kenkyū-buntansha) |
大塚 俊之 京都大学, ウイルス研究所, 助手 (20324709)
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| Project Period (FY) |
2003 – 2004
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| Project Status |
Completed (Fiscal Year 2004)
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| Budget Amount *help |
¥47,580,000 (Direct Cost: ¥36,600,000、Indirect Cost: ¥10,980,000)
Fiscal Year 2004: ¥19,760,000 (Direct Cost: ¥15,200,000、Indirect Cost: ¥4,560,000)
Fiscal Year 2003: ¥27,820,000 (Direct Cost: ¥21,400,000、Indirect Cost: ¥6,420,000)
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| Keywords | Biological clock / Oscillation / bHLH factor / 2-hour periodicity / Negative feedback / Hes1 / Hes7 / Somitogenesis / ネガティブ フィードバック |
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| Research Abstract |
The molecular mechanism for biological clocks that regulate embryogenesis has been only recently beginning to be elucidated. We have recently shown that the bHLH repressors Hes1 and Hes7 function as biological clocks with a periodicity of two hours. Hes1 and Hes7 autonomously exhibit two-hour cycle oscillatory expression. This oscillation could be simulated by the following equations.
dp(t)/dt=am(t-T_p)-bp(t)
dm(t)/dt=k/{1+{p(t-T_m}^2/po^2]-cm(t)
These equations are based on the negative feedback loop by a dimer of Hes proteins. These equations indicate that the instability of Hes proteins is essential for stable oscillation. The half-life of Hes proteins is about 20 min, but this simulation model predicts that if the half-life becomes 30 min, the oscillation could be damped. To determine the significance of the instability of Hes proteins, we generated transgenic mice, which express stabilized Hes7 protein (the half-life is about 30 min) instead of the wild-type Hes7. In these mice, Hes7 oscillation becomes damped after three or four cycles, and somites are fused. This result agrees well with the prediction of the simulation model.
To understand the roles of Hes oscillation in other systems than the somite segmentation, we searched for genes whose expression oscillates with a periodicity of two hours. RNA was extracted from cultured fibroblast cells at several time points after serum treatment and subjected to micro-array analysis. From this analysis, we identified about ten genes whose expression oscillates with a periodicity of two hours like Hes1. Oscillation of some genes is in the same phase as Hes1 while that of others is different. We are planning to elucidate their functions by over-expression and knock-down experiments. These experiments will lead to understanding of the significance of Hes oscillation in many biological systems.
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