Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA.
Mol Cell. 2009 Dec 11;36(5):872-84. doi: 10.1016/j.molcel.2009.11.017.
In response to Wnt stimulation, beta-catenin accumulates and activates target genes. Using modeling and experimental analysis, we found that the level of beta-catenin is sensitive to perturbations in the pathway, such that cellular variation would be expected to alter the signaling outcome. One unusual parameter was robust: the fold-change in beta-catenin level (post-Wnt/pre-Wnt). In Xenopus, dorsal-anterior development and target gene expression are robust to perturbations that alter the final level but leave the fold-change intact. These suggest, first, that despite cellular noise, the cell responds reliably to Wnt stimulation by maintaining a robust fold-change in beta-catenin. Second, the transcriptional machinery downstream of the Wnt pathway does not simply read the beta-catenin level after Wnt stimulation but computes fold-changes in beta-catenin. Analogous to Weber's Law in sensory physiology, some gene transcription networks must respond to fold-changes in signals, rather than absolute levels, which may buffer stochastic, genetic, and environmental variation.
针对 Wnt 的刺激，β-连环蛋白积累并激活靶基因。通过建模和实验分析，我们发现β-连环蛋白的水平对通路中的干扰很敏感，因此细胞的变异预计会改变信号转导的结果。一个不寻常的参数是稳健的：β-连环蛋白水平的变化倍数（Wnt 后/Wnt 前）。在爪蟾中，背-前发育和靶基因表达对改变最终水平但保持变化倍数不变的干扰具有稳健性。这首先表明，尽管存在细胞噪声，细胞通过维持β-连环蛋白的稳健变化倍数，可靠地对 Wnt 刺激做出反应。其次，Wnt 通路下游的转录机制在 Wnt 刺激后并不简单地读取β-连环蛋白水平，而是计算β-连环蛋白的变化倍数。类似于感觉生理学中的韦伯定律，一些基因转录网络必须对信号的变化倍数而不是绝对水平做出反应，这可能缓冲随机的、遗传的和环境的变异。
