Dynamic assignment and maintenance of positional identity in the ventral neural tube by the morphogen sonic hedgehog.
Dynamic assignment and maintenance of positional identity in the ventral neural tube by the morphogen sonic hedgehog.
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DOI：
10.1371/journal.pbio.1000382
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发表时间：
2010-06-01
期刊：
影响因子：
9.8
通讯作者：
Sasai N
中科院分区：
文献类型：
--
作者：
Dessaud E;Ribes V;Balaskas N;Yang LL;Pierani A;Kicheva A;Novitch BG;Briscoe J;Sasai N
在脊椎动物神经管的发展过程中，细胞不仅从声音刺猬信号传导梯度的空间水平，而且还从时间持续时间中获得了位置身份。
形态原是分泌的信号分子，以分级的方式作用，以控制发育组织中细胞分化的模式。一个例子是声波刺猬（SHH），它在包括中枢神经系统在内的几种发育中的脊椎动物组织中起作用，以在胚胎模式期间提供位置信息。在这里，我们解决了SHH信号如何在整个腹侧神经管中分配不同神经元亚型祖细胞的位置身份。细胞内信号转导和基因表达的测定表明，持续时间和信号水平对于形态学解释至关重要。腹侧神经元亚型的祖细胞依次建立，逐渐地腹侧身份需要相应更高的水平和更长的SHH信号传导。此外，如果信号水平低于阈值，则细胞在延长时间内对SHH信号变化的变化仍然敏感，从而恢复到先例身份。因此，信号的持续时间不仅对分配也很重要，而且对位置身份的完善和维护也很重要。数据共同提出了一个动态模型，用于腹神经管模式，其中位置信息与SHH信号的时间积分相对应。这表明了仅依赖信号水平的传统形态学作用模型的替代方法。
在许多发育中的组织中，产生细胞类型的模式取决于称为形态剂的分泌因子。这些信号分子是在特定位置和特定浓度下产生的，从而形成浓度梯度。不同的靶基因在距形态学源的特定距离处诱导，因此基因表达的空间模式与该浓度梯度相关。在这项研究中，我们研究了细胞如何对形态学梯度的反应以产生适当的细胞分化模式。我们专注于形态学声音刺猬（SHH），该刺猬（SHH）指定了神经管的腹侧区域（中枢神经系统的胚胎前体）的不同类型神经元的模式。我们表明，除了SHH的浓度外，SHH信号的持续时间还有助于腹侧神经管的图案。结果是，定义不同细胞身份的基因以特征性的时间进展表达。此外，需要持续的SHH信号传导才能进行更多的腹侧细胞类型。否则，它们恢复为以前的细胞身份。这些结果共同表明，SHH需要动态和持续的信号传导才能使腹神经管的图案构成，这挑战了形态学作用的常规模型，这些模型仅依赖于形态梯度中特定位置所感知的信号的浓度。
During development of the vertebrate neural tube, cells acquire their positional identity from not only the spatial level of the Sonic Hedgehog signaling gradient, but also the temporal duration. Morphogens are secreted signalling molecules that act in a graded manner to control the pattern of cellular differentiation in developing tissues. An example is Sonic hedgehog (Shh), which acts in several developing vertebrate tissues, including the central nervous system, to provide positional information during embryonic patterning. Here we address how Shh signalling assigns the positional identities of distinct neuronal subtype progenitors throughout the ventral neural tube. Assays of intracellular signal transduction and gene expression indicate that the duration as well as level of signalling is critical for morphogen interpretation. Progenitors of the ventral neuronal subtypes are established sequentially, with progressively more ventral identities requiring correspondingly higher levels and longer periods of Shh signalling. Moreover, cells remain sensitive to changes in Shh signalling for an extended time, reverting to antecedent identities if signalling levels fall below a threshold. Thus, the duration of signalling is important not only for the assignment but also for the refinement and maintenance of positional identity. Together the data suggest a dynamic model for ventral neural tube patterning in which positional information corresponds to the time integral of Shh signalling. This suggests an alternative to conventional models of morphogen action that rely solely on the level of signalling. In many developing tissues, the pattern in which cell types are generated depends on secreted factors called morphogens. These signalling molecules are produced in specific locations and at specific concentrations, thereby forming concentration gradients. Different target genes are induced at specific distances from the source of the morphogen, and therefore the spatial pattern of gene expression correlates with this concentration gradient. In this study, we examined how cells respond to a morphogen gradient to produce the appropriate pattern of cellular differentiation. We focused on the morphogen Sonic Hedgehog (Shh), which specifies the pattern of different types of neurons in the ventral regions of the neural tube (the embryo's precursor to the central nervous system). We show that in addition to the concentration of Shh, the duration of Shh signalling also contributes to the patterning of the ventral neural tube. A consequence of this is that the genes defining different cellular identities are expressed in a characteristic temporal progression. In addition, sustained Shh signalling is required for more ventral cell types; otherwise they revert to their previous cellular identity. Together these results indicate that dynamic and sustained signalling by Shh is required for the patterning of the ventral neural tube, challenging conventional models of morphogen action that rely solely on the concentration of signal perceived by cells at specific positions in the morphogen gradient.
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