Gene regulatory network interactions in sea urchin endomesoderm induction.
Gene regulatory network interactions in sea urchin endomesoderm induction.
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DOI：
10.1371/journal.pbio.1000029
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发表时间：
2009-02-03
期刊：
影响因子：
9.8
通讯作者：
Angerer, Lynne M.
中科院分区：
文献类型：
--
作者：
Sethi, Aditya J.;Angerer, Robert C.;Angerer, Lynne M.
当代胚胎发育研究的一个主要目标是了解伴随胚胎诱导现象的大量调控变化。高分辨率的海胆pregastrular内中胚层基因调控网络（EM-GRN）提供了一个独特的框架，研究全球监管的相互作用下的内中胚层诱导。海胆胚胎的植物性微粒构成了一个经典的内中胚层信号中心，其诱导原肠形成的潜力几乎在世纪前就被证明了。在这项工作中，我们通过错误表达微球决定簇Pmar 1异位激活在微球后代中运作的原代间充质细胞-GRN（PMC-GRN），并鉴定在动物卵裂球中诱导的响应EM-GRN。使用局部功能丧失分析结合endo 16的表达（微粒依赖性内中胚层特化的分子定义），我们表明TGFβ细胞因子激活素B是发出这种信号的卵裂球中这种诱导的重要组成部分，我们报道正常的前原肠胚内中胚层特化需要激活EM-1的Pmar 1诱导亚群，GRN由相同的细胞因子，强烈表明，早期微粒介导的内中胚层规范，调节海胆胚胎中的原肠胚形成的及时，也激活素B依赖。这项研究意外地发现了存在一个额外的未表征的micromere信号的内中胚层祖细胞，显着修改现有的模型。在第一个网络水平的表征细胞间的诱导现象之一，我们描述了一个重要的体内模型的要求激活素B信号在胚胎内中胚层祖规范的最早阶段。近年来，“基因调控网络”（GRN）提供了控制生物过程的基因相互作用的综合观点。在发育中的合子中最早被激活的网络之一是控制内中胚层发育的网络。在海胆中，这个网络包括几个子网络，它们在形成发育胚胎的内胚层和中胚层的相邻细胞层中发挥作用。虽然经典的胚胎学操作已经表明，胚胎骨骼的前体诱导相邻细胞的内中胚层命运，但调节这种相互作用的GRNs尚不清楚。为了研究这些网络，我们异位激活了GRN，其在成骨前体中起作用，并表征了邻近细胞中的响应GRN，这些细胞采用内中胚层命运。通过测试响应GRN中每个核心因子的响应性，这使我们能够识别执行对诱导的响应的子集，我们证明了信号分子ActivinB是这种诱导的重要组成部分，并且其功能是生理相关的：在正常胚胎发育期间需要激活响应骨骼生成前体信号的相同GRN。此外，对激活素B信号传导的网络响应揭示了骨骼生成前体发出的额外的未表征的诱导信号的更大复杂性。因此，我们的研究结果强调了如何相互作用的GRNs可以用来理解一个基本的信号转导过程。一个经典的胚胎诱导海胆描述在相互作用的基因调控网络和信号转导系统，连接它们。
A major goal of contemporary studies of embryonic development is to understand large sets of regulatory changes that accompany the phenomenon of embryonic induction. The highly resolved sea urchin pregastrular endomesoderm–gene regulatory network (EM-GRN) provides a unique framework to study the global regulatory interactions underlying endomesoderm induction. Vegetal micromeres of the sea urchin embryo constitute a classic endomesoderm signaling center, whose potential to induce archenteron formation from presumptive ectoderm was demonstrated almost a century ago. In this work, we ectopically activate the primary mesenchyme cell–GRN (PMC-GRN) that operates in micromere progeny by misexpressing the micromere determinant Pmar1 and identify the responding EM-GRN that is induced in animal blastomeres. Using localized loss-of -function analyses in conjunction with expression of endo16, the molecular definition of micromere-dependent endomesoderm specification, we show that the TGFβ cytokine, ActivinB, is an essential component of this induction in blastomeres that emit this signal, as well as in cells that respond to it. We report that normal pregastrular endomesoderm specification requires activation of the Pmar1-inducible subset of the EM-GRN by the same cytokine, strongly suggesting that early micromere-mediated endomesoderm specification, which regulates timely gastrulation in the sea urchin embryo, is also ActivinB dependent. This study unexpectedly uncovers the existence of an additional uncharacterized micromere signal to endomesoderm progenitors, significantly revising existing models. In one of the first network-level characterizations of an intercellular inductive phenomenon, we describe an important in vivo model of the requirement of ActivinB signaling in the earliest steps of embryonic endomesoderm progenitor specification. In recent years, “gene regulatory networks” (GRNs) have provided integrated views of gene interactions that control biological processes. One of the earliest networks to be activated in the developing zygotes is the one controlling endomesoderm development. In the sea urchin, this network includes several subnetworks that function in adjacent tiers of cells that form the endoderm and mesoderm of the developing embryo. Although classic embryological manipulations have shown that the precursors of the embryonic skeleton induce endomesoderm fate in adjacent cells, the GRNs regulating this interaction are not understood. To investigate these networks, we ectopically activated a GRN that operates in skeletogenic precursors and characterized the responding GRN in neighboring cells, which adopt an endomesoderm fate. By testing the responsiveness of every core factor in the responding GRN, which allowed us to identify a subset that executes the response to the induction, we demonstrated that the signaling molecule, ActivinB, is an essential component of this induction and that its function is physiologically relevant: it is required during normal embryonic development to activate the same GRN that responds to signals from skeletogenic precursors. Furthermore, the network response to ActivinB signaling reveals greater complexity in an additional uncharacterized inductive signal emitted by skeletogenic precursors. Our results thus highlight how interacting GRNs can be used to understand a fundamental signaling process. A classic embryonic induction in sea urchins is described in terms of interacting gene regulatory networks and a signal transduction system that connects them.
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DOI：
10.1073/pnas.0801201105
发表时间：
2008-04-22
影响因子：
11.1
作者：
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影响因子：
2.7
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DOI：
10.1073/pnas.0705505104
发表时间：
2007-07-31
影响因子：
11.1
作者：
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通讯作者：
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影响因子：
9.8
作者：
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