Feedback Control of Gene Expression Variability in the Caenorhabditis elegans Wnt Pathway
Feedback Control of Gene Expression Variability in the Caenorhabditis elegans Wnt Pathway
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DOI：
10.1016/j.cell.2013.09.060
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发表时间：
2013-11-07
期刊：
影响因子：
64.5
通讯作者：
van Oudenaarden, Alexander
中科院分区：
文献类型：
--
作者：
Ji, Ni;Middelkoop, Teije C.;van Oudenaarden, Alexander
即使在等基因群体中，基因表达的变异性也会导致表型异质性。在这里，我们利用秀丽隐杆线虫Q神经母细胞的定型、Wnt信号依赖性发育来探索控制基因表达变异性的内源性机制。我们发现，在Wnt通路活性受到干扰的突变体中，引导Q神经母细胞迁移的关键Hox基因表现出增加的基因表达变异性。基因表达分布的独特特征促使我们系统地寻找调控相互作用，揭示了一个连锁的正反馈和负反馈循环网络。有趣的是，正反馈似乎与负反馈合作，以减少变异，同时保持Hox基因表达在较高水平。一个最小模型正确地预测了突变体之间基因表达变异性的增加。我们的研究结果强调了基因网络结构对表达变异性的影响，并暗示反馈调节是确保发育稳健性的有效机制。
Variability in gene expression contributes to phenotypic heterogeneity even in isogenic populations. Here, we used the stereotyped, Wnt signaling-dependent development of the Caenorhabditis elegans Q neuroblast to probe endogenous mechanisms that control gene expression variability. We found that the key Hox gene that orients Q neuroblast migration exhibits increased gene expression variability in mutants in which Wnt pathway activity has been perturbed. Distinct features of the gene expression distributions prompted us on a systematic search for regulatory interactions, revealing a network of interlocked positive and negative feedback loops. Interestingly, positive feedback appeared to cooperate with negative feedback to reduce variability while keeping the Hox gene expression at elevated levels. A minimal model correctly predicts the increased gene expression variability across mutants. Our results highlight the influence of gene network architecture on expression variability and implicate feedback regulation as an effective mechanism to ensure developmental robustness.