The Sonic hedgehog signaling system as a bistable genetic switch
The Sonic hedgehog signaling system as a bistable genetic switch
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DOI：
10.1016/s0006-3495(04)74328-3
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发表时间：
2004-05-01
影响因子：
3.4
通讯作者：
Schaffer, DV
中科院分区：
文献类型：
--
作者：
Lai, K;Robertson, MJ;Schaffer, DV
声波刺猬 (Shh) 控制着许多系统中不同命运之间的关键细胞决策，特别是在干细胞中。 Shh网络的功能就像一个基因开关，我们从理论上和计算上分析了它的结构如何赋予它在Shh浓度阈值下切换命运选择的能力。该网络由嵌入负信号反馈环中的正转录反馈环组成。具体来说，转录因子 Gli 的正反馈会上调其自身的表达，从而导致一个开关，该开关可以根据 Shh 采取两种不同的状态。然而，Gli 也会上调信号抑制因子 Patched，负反馈抑制强大的 Gli 自动调节循环。预计与癌症相关的突变会不可逆转地转变为高 Gli 状态。最后，随机模拟揭示了负补丁反馈环路在抑制 Gli 波动方面发挥着关键作用，以减少自发状态切换并保持网络稳健的、类似开关的行为。许多信号系统中都存在紧密相连的正反馈环和负反馈环，因此Shh系统可能代表大量基因调控网络，这些网络控制着干细胞在整个发育和成年期的命运。
Sonic hedgehog (Shh) controls critical cellular decisions between distinct fates in many systems, particularly in stem cells. The Shh network functions as a genetic switch, and we have theoretically and computationally analyzed how its structure can endow it with the ability to switch fate choices at a threshold Shh concentration. The network is composed of a positive transcriptional feedback loop embedded within a negative signaling feedback loop. Specifically, positive feedback by the transcription factor Gli, which upregulates its own expression, leads to a switch that can adopt two distinct states as a function of Shh. However, Gli also upregulates the signaling repressor Patched, negative feedback that reins in the strong Gli autoregulatory loop. Mutations that have been associated with cancer are predicted to yield an irreversible switch to a high Gli state. Finally, stochastic simulation reveals the negative Patched feedback loop serves a critical function of dampening Gli fluctuations to reduce spontaneous state switching and preserve the network's robust, switch-like behavior. Tightly linked positive and negative feedback loops are present in many signaling systems, and the Shh system is therefore likely representative of a large set of gene regulation networks that control stem cell fate throughout development and into adulthood.