Genetic and systems level analysis of Drosophila sticky/citron kinase and dFmr1 mutants reveals common regulation of genetic networks.
Genetic and systems level analysis of Drosophila sticky/citron kinase and dFmr1 mutants reveals common regulation of genetic networks.
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DOI：
10.1186/1752-0509-2-101
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发表时间：
2008-11-25
影响因子：
--
通讯作者：
Bosco G
中科院分区：
文献类型：
--
作者：
Bauer CR;Epstein AM;Sweeney SJ;Zarnescu DC;Bosco G
在果蝇中，基因Sticky和dFmr1都被证明调节细胞骨架的动力学和染色质结构。这些基因还与ArgAerte家族的microRNA调节剂在基因上相互作用。此外，在哺乳动物系统中，这两个基因都与神经元发育有关。鉴于这些遗传和功能上的相似性，我们测试了果蝇Sticky和dFmr1的遗传相互作用，并测量了这两个突变体的全基因组表达，以评估基因调控方面的相似性。我们发现，在发育中的眼睛中，粘性突变可以主要抑制dFmr1的功能获得表型，而dFmr1 RNAi和dFmr1功能缺失突变增强了粘性的RNAi所产生的表型。我们还发现在两个突变体中都有大量错误表达的转录本，这表明粘滞和dFmr1基因产物类似地调控基因表达。通过将基因表达数据与蛋白质-蛋白质相互作用网络相结合，我们发现Sticky和dFmr1的突变导致了常见基因网络的错误表达，从而预测了以前未发现与这两个基因相关的其他特定表型。进一步的表型分析证实了这些预测。这些发现在两个以前不相关的基因之间建立了功能联系。微阵列分析表明，Sticky和dFmr1都是调节多种细胞类型中的许多发育基因所必需的。这两个基因调控的转录本的多样性表明了粘滞和dFmr1突变体表现出多效性的明显原因，并提供了许多关于这些基因功能的新的、可测试的假说。由于这两个基因都与哺乳动物大脑的发育和功能有关，因此这些结果与人类健康有关，也与理解更一般的生物过程有关。
In Drosophila, the genes sticky and dFmr1 have both been shown to regulate cytoskeletal dynamics and chromatin structure. These genes also genetically interact with Argonaute family microRNA regulators. Furthermore, in mammalian systems, both genes have been implicated in neuronal development. Given these genetic and functional similarities, we tested Drosophila sticky and dFmr1 for a genetic interaction and measured whole genome expression in both mutants to assess similarities in gene regulation. We found that sticky mutations can dominantly suppress a dFmr1 gain-of-function phenotype in the developing eye, while phenotypes produced by RNAi knock-down of sticky were enhanced by dFmr1 RNAi and a dFmr1 loss-of-function mutation. We also identified a large number of transcripts that were misexpressed in both mutants suggesting that sticky and dFmr1 gene products similarly regulate gene expression. By integrating gene expression data with a protein-protein interaction network, we found that mutations in sticky and dFmr1 resulted in misexpression of common gene networks, and consequently predicted additional specific phenotypes previously not known to be associated with either gene. Further phenotypic analyses validated these predictions. These findings establish a functional link between two previously unrelated genes. Microarray analysis indicates that sticky and dFmr1 are both required for regulation of many developmental genes in a variety of cell types. The diversity of transcripts regulated by these two genes suggests a clear cause of the pleiotropy that sticky and dFmr1 mutants display and provides many novel, testable hypotheses about the functions of these genes. As both of these genes are implicated in the development and function of the mammalian brain, these results have relevance to human health as well as to understanding more general biological processes.
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影响因子：
16.2
作者：
Dockendorff, TC;Su, HS;Jongens, TA
通讯作者：
Jongens, TA
影响因子：
10.5
作者：
Ghabrial, A;Ray, RP;Schüpbach, T
通讯作者：
Schüpbach, T
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3.7
作者：
LoTurco, JJ;Sarkisian, MR;Bai, JL
通讯作者：
Bai, JL
影响因子：
11.8
作者：
Klattenhoff, Carla;Bratu, Diana P.;Theurkauf, William E.
通讯作者：
Theurkauf, William E.
影响因子：
56.9
作者：
Kazemi-Esfarjani, P;Benzer, S
通讯作者：
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