Canalization of gene expression in the Drosophila blastoderm by gap gene cross regulation.
Canalization of gene expression in the Drosophila blastoderm by gap gene cross regulation.
复制标题
通过间隙基因交叉调节，基因表达在果蝇芽孢杆菌中进行了渠道化。
DOI：
10.1371/journal.pbio.1000049
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发表时间：
2009-03
期刊：
影响因子：
9.8
通讯作者：
Reinitz J
中科院分区：
文献类型：
--
作者：
Manu;Surkova S;Spirov AV;Gursky VV;Janssens H;Kim AR;Radulescu O;Vanario-Alonso CE;Sharp DH;Samsonova M;Reinitz J
发育中的胚胎表现出强大的能力来减少自然发生或作为实验操作的结果的表型变异。这种变异的减少是通过一种被称为管道化的表观遗传机制发生的，由于缺乏必要的分子数据和适当的基因调控模型，这种现象一直难以理解。近年来，果蝇胚层片段确定过程的定量基因表达数据已经可用，揭示了管道化的具体实例。这些数据表明，与早期水平相比，在原肠胚形成开始时，合子片段基因表达模式的变化明显减少，这种变化明显低于母体蛋白梯度Bicoid的变化。利用基因调控的预测动力学模型，研究了Bicoid变异对下游间隙基因的影响。该模型正确地预测了间隙基因表达模式的减少变异，并允许表征管道机制。我们表明，沟通化是合子间隙基因之间特定调控相互作用的结果。我们证明了这一解释的有效性，通过表明变异在两个间隙基因kr<s:1> ppel和knirps突变的胚胎中增加，反驳了管道化是由于未发现的形态原，或者根本没有发生的竞争性建议。在《公共科学图书馆计算生物学》（doi:10.1371/journal.pcbi）的一篇附带文章中。（1000303），我们发现间隙基因之间的交叉调控使它们的表达接近动态吸引子，减少了初始变异并提供了稳健的输出。这些结果表明，Bicoid梯度不足以产生具有低方差的间隙基因边界，而这种低方差是由间隙基因交叉调控产生的。更一般地说，我们表明复杂的多基因渠化现象可以通过应用精确的动力学模型在定量和预测水平上理解。动物有一种惊人的能力，尽管在胚胎发生过程中条件多变，但仍能可靠地发育。60多年前，有人提出，这种被称为沟管化的发育特性是基因相互作用的结果，基因相互作用调节生化反应，从而产生可靠的结果。从那时起，在理解基因型和环境变异的缓冲方面取得了很大进展，揭示变异的个体突变已经被确定。然而，遗传相互作用产生沟通化的机制尚未得到很好的理解，因为这需要多种发育决定因素的分子数据和正确预测复杂相互作用的模型。我们利用基因表达数据在高空间和时间分辨率参与果蝇的分割的缺口基因。我们还应用数学模型表明，间隙基因之间的交叉调控是该系统渠化的主要原因。此外，该模型预测了导致运河化的特定相互作用，并通过实验验证了该预测。我们的研究结果表明，基因组可以相互作用以减少变异，并突出了遗传网络在产生健壮发育中的重要性。在果蝇的发育过程中，gap基因的表达模式比Bicoid形态梯度的变化要小得多。模型和实验表明，这种特定的通道化或发育稳健性是通过间隙基因交叉调控发生的。
Developing embryos exhibit a robust capability to reduce phenotypic variations that occur naturally or as a result of experimental manipulation. This reduction in variation occurs by an epigenetic mechanism called canalization, a phenomenon which has resisted understanding because of a lack of necessary molecular data and of appropriate gene regulation models. In recent years, quantitative gene expression data have become available for the segment determination process in the Drosophila blastoderm, revealing a specific instance of canalization. These data show that the variation of the zygotic segmentation gene expression patterns is markedly reduced compared to earlier levels by the time gastrulation begins, and this variation is significantly lower than the variation of the maternal protein gradient Bicoid. We used a predictive dynamical model of gene regulation to study the effect of Bicoid variation on the downstream gap genes. The model correctly predicts the reduced variation of the gap gene expression patterns and allows the characterization of the canalizing mechanism. We show that the canalization is the result of specific regulatory interactions among the zygotic gap genes. We demonstrate the validity of this explanation by showing that variation is increased in embryos mutant for two gap genes, Krüppel and knirps, disproving competing proposals that canalization is due to an undiscovered morphogen, or that it does not take place at all. In an accompanying article in PLoS Computational Biology (doi:10.1371/journal.pcbi.1000303), we show that cross regulation between the gap genes causes their expression to approach dynamical attractors, reducing initial variation and providing a robust output. These results demonstrate that the Bicoid gradient is not sufficient to produce gap gene borders having the low variance observed, and instead this low variance is generated by gap gene cross regulation. More generally, we show that the complex multigenic phenomenon of canalization can be understood at a quantitative and predictive level by the application of a precise dynamical model. Animals have an astonishing ability to develop reliably in spite of variable conditions during embryogenesis. More than 60 years ago, it was proposed that this property of development, called canalization, results from genetic interactions that adjust biochemical reactions so as to bring about reliable outcomes. Since then, a great deal of progress has been made in understanding the buffering of genotypic and environmental variation, and individual mutations that reveal variation have been identified. However, the mechanisms by which genetic interactions produce canalization are not yet well understood, because this requires molecular data on multiple developmental determinants and models that correctly predict complex interactions. We make use of gene expression data at both high spatial and temporal resolution for the gap genes involved in the segmentation of Drosophila. We also apply a mathematical model to show that cross regulation among the gap genes is responsible for canalization in this system. Furthermore, the model predicted specific interactions that cause canalization, and the prediction was validated experimentally. Our results show that groups of genes can act on one another to reduce variation and highlights the importance of genetic networks in generating robust development. DuringDrosophila development, the expression patterns of gap genes are much less variable than the Bicoid morphogen gradient. Modeling and experiments show that this specific instance of canalization or developmental robustness occurs by gap gene cross regulation.
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影响因子：
64.8
作者：
HULSKAMP, M;PFEIFLE, C;TAUTZ, D
通讯作者：
TAUTZ, D
DOI：
10.1073/pnas.0509483102
发表时间：
2005-12-20
影响因子：
11.1
作者：
Gregor, T;Bialek, W;Wieschaus, EF
通讯作者：
Wieschaus, EF
影响因子：
64.8
作者：
Clyde, DE;Corado, MSG;Small, S
通讯作者：
Small, S
影响因子：
2
作者：
Hardway, Heather;Mukhopadhyay, Bibhash;Forman, Robin
通讯作者：
Forman, Robin
影响因子：
64.5
作者：
DRIEVER, W;NUSSLEINVOLHARD, C
通讯作者：
NUSSLEINVOLHARD, C