Spatial analysis of expression patterns predicts genetic interactions at the mid-hindbrain boundary.
Spatial analysis of expression patterns predicts genetic interactions at the mid-hindbrain boundary.
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表达模式的空间分析可以预测中后脑边界处的遗传相互作用。
DOI：
10.1371/journal.pcbi.1000569
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发表时间：
2009-11
影响因子：
4.3
通讯作者：
Theis, Fabian J.
中科院分区：
文献类型：
--
作者：
Wittmann, Dominik M.;Bloechl, Florian;Truembach, Dietrich;Wurst, Wolfgang;Prakash, Nilima;Theis, Fabian J.
峡部组织者介导脊椎动物发育过程中中脑和后脑的分化，其特征在于围绕中脑-后脑边界（MHB）的局部限制性基因表达结构域的明确模式。这种模式是由几种转录和分泌因子之间的调控网络建立和维持的，但尚未完全了解。在这方面的贡献，我们表明，在小鼠MHB的特征空间基因表达模式的布尔分析揭示了在这个网络中的关键调控相互作用。我们的分析采用了计算逻辑的技术，用于布尔函数的最小化。这种方法使我们能够预测各种监管相互作用的相互作用。特别是，我们预测Fgf 8对Wnt 1表达的维持作用，而不是诱导作用，这一问题在已发表的数据中仍不清楚。使用小鼠前神经板/管外植体培养，我们提供的实验证据表明，FGF 8事实上只维持，但不诱导异位Wnt 1在这些外植体的表达。结合先前验证的相互作用，这一发现允许在MHB的关键转录和分泌因子之间构建调控网络。布尔，微分方程和反应扩散模型的分析，这个网络证实，它确实能够解释稳定的维护MHB以及表达模式的时间过程中，无论是在野生型和各种敲除条件。总之，我们表明，类似的时间也空间的表达模式可以用来获得信息的结构调控网络。我们发现，特别是，周围的MHB的空间基因表达模式，帮助我们了解这个边界上的系统水平的维护。了解大脑在发育过程中的形成是一个诱人的挑战。它对于对抗神经退行性疾病也至关重要。在脊椎动物中，中枢神经系统起源于一种称为神经板的结构。该组织分为四个区域，继续发育为前脑、中脑、后脑和脊髓。局部表达的基因和信号分子之间的相互作用是这种模式的原因。这个过程中的两个关键信号分子是Fgf 8和Wnt 1蛋白。它们从位于预期中脑和后脑之间的边界（中脑-后脑边界，MHB）的信号中心分泌，并介导这两个脑区域的发育。在这里，我们逻辑分析的空间基因表达模式在MHB和预测的相互作用参与分化的中脑和后脑。特别是，我们的分析表明，Wnt 1依赖于Fgf 8的稳定维护。在小鼠神经板/管外植体中植入Fgf 8包被的珠子后Wnt 1表达的时程分析实验验证了我们关于这两个关键图案化分子之间相互作用的预测。随后，我们证明，可用的数据可以构建一个数学模型，能够解释在MHB的信号中心的维护。我们开始在系统层面上理解大脑形成的这个小方面。
The isthmic organizer mediating differentiation of mid- and hindbrain during vertebrate development is characterized by a well-defined pattern of locally restricted gene expression domains around the mid-hindbrain boundary (MHB). This pattern is established and maintained by a regulatory network between several transcription and secreted factors that is not yet understood in full detail. In this contribution we show that a Boolean analysis of the characteristic spatial gene expression patterns at the murine MHB reveals key regulatory interactions in this network. Our analysis employs techniques from computational logic for the minimization of Boolean functions. This approach allows us to predict also the interplay of the various regulatory interactions. In particular, we predict a maintaining, rather than inducing, effect of Fgf8 on Wnt1 expression, an issue that remained unclear from published data. Using mouse anterior neural plate/tube explant cultures, we provide experimental evidence that Fgf8 in fact only maintains but does not induce ectopic Wnt1 expression in these explants. In combination with previously validated interactions, this finding allows for the construction of a regulatory network between key transcription and secreted factors at the MHB. Analyses of Boolean, differential equation and reaction-diffusion models of this network confirm that it is indeed able to explain the stable maintenance of the MHB as well as time-courses of expression patterns both under wild-type and various knock-out conditions. In conclusion, we demonstrate that similar to temporal also spatial expression patterns can be used to gain information about the structure of regulatory networks. We show, in particular, that the spatial gene expression patterns around the MHB help us to understand the maintenance of this boundary on a systems level. Understanding brain formation during development is a tantalizing challenge. It is also essential for the fight against neurodegenerative diseases. In vertebrates, the central nervous system arises from a structure called the neural plate. This tissue is divided into four regions, which continue to develop into forebrain, midbrain, hindbrain and spinal cord. Interactions between locally expressed genes and signaling molecules are responsible for this patterning. Two key signaling molecules in this process are Fgf8 and Wnt1 proteins. They are secreted from a signaling center located at the boundary between prospective mid- and hindbrain (mid-hindbrain boundary, MHB) and mediate development of these two brain regions. Here, we logically analyze the spatial gene expression patterns at the MHB and predict interactions involved in the differentiation of mid- and hindbrain. In particular, our analysis indicates that Wnt1 depends on Fgf8 for stable maintenance. A time-course analysis of Wnt1 expression after implantation of Fgf8-coated beads in mouse neural plate/tube explants experimentally validates our prediction about the interactions between these two key patterning molecules. Subsequently, we demonstrate that available data allows construction of a mathematical model able to explain the maintenance of the signaling center at the MHB. We begin to understand this small aspect of brain formation on a systems level.
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DOI：
10.1073/pnas.93.24.13870
发表时间：
1996-11-26
影响因子：
11.1
作者：
Favor, J;Sandulache, R;Schughart, K
通讯作者：
Schughart, K
影响因子：
64.8
作者：
Broccoli, V;Boncinelli, E;Wurst, W
通讯作者：
Wurst, W
影响因子：
64.8
作者：
Danielian, PS;McMahon, AP
通讯作者：
McMahon, AP
影响因子：
10.5
作者：
DAVIS, CA;NOBLETOPHAM, SE;JOYNER, AL
通讯作者：
JOYNER, AL
影响因子：
4.8
作者：
Gemel, J;Jacobsen, C;MacArthur, CA
通讯作者：
MacArthur, CA