Dynamic interpretation of hedgehog signaling in the Drosophila wing disc.
Dynamic interpretation of hedgehog signaling in the Drosophila wing disc.
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DOI：
10.1371/journal.pbio.1000202
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发表时间：
2009-09
期刊：
影响因子：
9.8
通讯作者：
Stathopoulos A
中科院分区：
文献类型：
--
作者：
Nahmad M;Stathopoulos A
果蝇细胞对刺猬形态的反应不仅取决于任何给定时间的形态浓度的精确测量，还取决于细胞暴露于形态学的历史。
形态剂在经典上定义为通过在距离浓度依赖性方式调节基因表达的远距离表达的分子。并指定基因表达的至少三个不同的结构域提供的证据表明，HH信号的解释取决于对HH的暴露历史，并且建议单个浓度阈值足以支持多个输出，我们预测，在稳态下，只能定义两个域。 HH，表明两个或多个基因表达模式的边界不能由静态HH梯度指定。通过对HH靶基因表达的临时检查HH稳态梯度，我们观察到这些模式最初会在前方扩展，然后进行完善，从而在体内证据表明HH基因网络体系结构是由HH造成的。 - 接收器的依赖性上调（PTC）。在野生型盘上具有独特的边界，我们的结果支持了一个模型，其中HH梯度动力学是由PTC上调引起的，在基因表达模式的建立中起着教学作用。
发育中的胚胎中的细胞需要有关其其他细胞的位置，以便通过测量称为Mopphogens的局部信号分子的局部浓度来获取该位置信息。果蝇果蝇果皮狗司机，信号分子刺猬沿着前轴的浓度梯度分布，但指定了至少三个不同的基因表达结构域。表达结构域，这些模式的边界与局部刺猬浓度之间的直接对应关系尚未使用刺猬信号网络的计算机模拟，我们提供了证据表明，静态形态梯度的直接灵敏度不足以指定观察到的细胞反应。他们先前的刺猬历史。我们提供了支持我们模型的实验证据，并包含该系统中刺猬依赖性图案所必需的梯度动力学。
Drosophila cell response to the Hedgehog morphogen depends not just on a precise measurement of morphogen concentration at any given time, but instead on the history of cell exposure to morphogen. Morphogens are classically defined as molecules that control patterning by acting at a distance to regulate gene expression in a concentration-dependent manner. In the Drosophila wing imaginal disc, secreted Hedgehog (Hh) forms an extracellular gradient that organizes patterning along the anterior–posterior axis and specifies at least three different domains of gene expression. Although the prevailing view is that Hh functions in the Drosophila wing disc as a classical morphogen, a direct correspondence between the borders of these patterns and Hh concentration thresholds has not been demonstrated. Here, we provide evidence that the interpretation of Hh signaling depends on the history of exposure to Hh and propose that a single concentration threshold is sufficient to support multiple outputs. Using mathematical modeling, we predict that at steady state, only two domains can be defined in response to Hh, suggesting that the boundaries of two or more gene expression patterns cannot be specified by a static Hh gradient. Computer simulations suggest that a spatial “overshoot” of the Hh gradient occurs, i.e., a transient state in which the Hh profile is expanded compared to the Hh steady-state gradient. Through a temporal examination of Hh target gene expression, we observe that the patterns initially expand anteriorly and then refine, providing in vivo evidence for the overshoot. The Hh gene network architecture suggests this overshoot results from the Hh-dependent up-regulation of the receptor, Patched (Ptc). In fact, when the network structure was altered such that the ptc gene is no longer up-regulated in response to Hh-signaling activation, we found that the patterns of gene expression, which have distinct borders in wild-type discs, now overlap. Our results support a model in which Hh gradient dynamics, resulting from Ptc up-regulation, play an instructional role in the establishment of patterns of gene expression. Cells in a developing embryo require information about their position with respect to other cells in order to function and differentiate appropriately. The predominant current model suggests that cells acquire this positional information by measuring the local concentration of signaling molecules called morphogens. In the developing wing of the fruit fly Drosophila melanogaster, the signaling molecule Hedgehog is distributed in a concentration gradient along the anterior–posterior axis and specifies at least three different domains of gene expression. Although there is a clear correlation between the Hedgehog extracellular gradient and the location of these gene expression domains, a direct correspondence between the borders of these patterns and local Hedgehog concentrations has not been demonstrated. Using computer simulations of the Hedgehog signaling network, we provide evidence that direct sensing of a static morphogen gradient is not sufficient to specify the observed cellular responses. We propose instead an alternative model for how cells define their position by interpreting the Hedgehog gradient. Our model suggests that, rather than simply make a precise measurement of the morphogen concentration to which cells are exposed at any given time, cells instead take into account their previous history of Hedgehog exposure. We provide experimental evidence that supports our model, and conclude that gradient dynamics are required for Hedgehog-dependent patterning in this system.
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