An insulin-to-insulin regulatory network orchestrates phenotypic specificity in development and physiology.
An insulin-to-insulin regulatory network orchestrates phenotypic specificity in development and physiology.
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DOI：
10.1371/journal.pgen.1004225
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发表时间：
2014-03
期刊：
影响因子：
4.5
通讯作者：
Ch'ng Q
中科院分区：
文献类型：
--
作者：
Fernandes de Abreu DA;Caballero A;Fardel P;Stroustrup N;Chen Z;Lee K;Keyes WD;Nash ZM;López-Moyado IF;Vaggi F;Cornils A;Regenass M;Neagu A;Ostojic I;Liu C;Cho Y;Sifoglu D;Shen Y;Fontana W;Lu H;Csikasz-Nagy A;Murphy CT;Antebi A;Blanc E;Apfeld J;Zhang Y;Alcedo J;Ch'ng Q
胰岛素样肽(ILPS)在发育和生理中发挥着高度保守的作用。大多数动物基因组编码多个ILP。在这里，我们确定了40种秀丽线虫ILPS如何协调不同过程的机制，包括发育、繁殖、寿命和几种特定的应激反应。我们的系统研究为这些表型确定了一种基于ILP的组合编码，其特征是显著的功能特异性和多样性，而不是全球冗余。值得注意的是，我们发现ILP在转录上相互调节，发现了ILP到ILP的调控网络，该网络支撑着ILP家族的组合表型编码。对ILP之间遗传相互作用的广泛分析揭示了它们的信号是如何整合的。对这些功能和调节ILP相互作用的综合分析确定了并行工作并通过串扰、反馈和补偿进行交互的局部遗传电路。这个组织为我们观察到的组合表型编码的表型特异性和分级调节提供了紧急机制。我们的发现也为大型荷尔蒙网络如何调节不同的特征提供了洞察力。胰岛素信号广泛参与多种动物从新陈代谢到长寿等多种生理过程的调节。许多动物都有多种胰岛素样多肽，可以调节这一信号通路的活性。例如，人类有10种，包括研究得很好的胰岛素激素，而线虫秀丽线虫有40种这样的多肽。这些胰岛素样多肽之间的相似性导致了一种主要的概念，即这些多肽之间存在广泛的冗余。与这一概念相反，我们发现线虫体内的40个胰岛素样肽对8种不同的生理输出具有特定和独特的影响，这些生理输出范围从发育、胁迫反应、寿命和繁殖。有趣的是，我们还发现这些多肽在转录水平上相互调节，形成一个信号网络。此外，我们观察到该网络被组织成并联电路，其活动受到补偿、反馈和串扰的影响。最后，网络的组织有助于解释不同的多肽组合如何产生特定的输出，并捕捉到这些多肽如何通过不同的多肽对多肽信号通路协调动物生理的复杂性。
Insulin-like peptides (ILPs) play highly conserved roles in development and physiology. Most animal genomes encode multiple ILPs. Here we identify mechanisms for how the forty Caenorhabditis elegans ILPs coordinate diverse processes, including development, reproduction, longevity and several specific stress responses. Our systematic studies identify an ILP-based combinatorial code for these phenotypes characterized by substantial functional specificity and diversity rather than global redundancy. Notably, we show that ILPs regulate each other transcriptionally, uncovering an ILP-to-ILP regulatory network that underlies the combinatorial phenotypic coding by the ILP family. Extensive analyses of genetic interactions among ILPs reveal how their signals are integrated. A combined analysis of these functional and regulatory ILP interactions identifies local genetic circuits that act in parallel and interact by crosstalk, feedback and compensation. This organization provides emergent mechanisms for phenotypic specificity and graded regulation for the combinatorial phenotypic coding we observe. Our findings also provide insights into how large hormonal networks regulate diverse traits. Insulin signaling is widely implicated in regulating diverse physiological processes ranging from metabolism to longevity across many animal species. Many animals have multiple insulin-like peptides that can regulate the activity of this signaling pathway. For example, while humans have ten, including the well-studied insulin hormone, the nematode Caenorhabditis elegans has forty such peptides. The similarity among these insulin-like peptides led to the predominant notion that widespread redundancy occurs among these peptides. Contrary to this notion, we find that the forty insulin-like peptides in the nematode C. elegans have specific and distinct effects on eight different physiological outputs that range from development, stress responses, lifespan and reproduction. Interestingly, we also find that these peptides regulate each other at the transcriptional level to form a signaling network. In addition, we observe that this network is organized into parallel circuits, whose activities are affected by compensation, feedback and crosstalk. Finally, the organization of the network helps to explain how different combinations of peptides generate specific outputs and captures the complexity of how these peptides orchestrate an animal's physiology through distinct peptide-to-peptide signaling circuits.
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影响因子：
7.8
作者：
Bai H;Kang P;Tatar M
通讯作者：
Tatar M
DOI：
10.1038/ismej.2012.135
发表时间：
2013-03
期刊：
The ISME journal
影响因子：
--
作者：
通讯作者：
--
影响因子：
56.9
作者：
Garsin, DA;Villanueva, JM;Ausubel, FM
通讯作者：
Ausubel, FM
影响因子：
9.2
作者：
Brogiolo, W;Stocker, H;Hafen, E
通讯作者：
Hafen, E
影响因子：
4.3
作者：
Baker, R. E.;Maini, P. K.
通讯作者：
Maini, P. K.