Extended exposure to Sonic hedgehog is required for patterning the posterior digits of the vertebrate limb
Extended exposure to Sonic hedgehog is required for patterning the posterior digits of the vertebrate limb
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DOI：
10.1016/j.ydbio.2007.05.030
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发表时间：
2007-08-15
影响因子：
2.7
通讯作者：
Tabin, Clifford J.
中科院分区：
文献类型：
--
作者：
Scherz, Paul J.;McGlinn, Edwina;Tabin, Clifford J.
音刺猬（Shh）是脊椎动物肢芽前后轴沿着建立不同趾命运的关键信号。虽然在传统的形态发生样反应中，前指似乎是由不同浓度的Shh指定的，但最近的研究表明，后指是由长时间暴露于Shh指定的，而不是Shh的阈值浓度。这种数字模式依赖于持续的Shh信号在后肢通过中期到晚期的芽阶段。我们发现，cyclopamine，一个有效的拮抗剂Shh信号，可以下调刺猬靶基因在后肢的整个时间Shh的表达，表明持续活跃的Shh信号确实发生。为了进一步探索肢体发育过程中Shh的时间和浓度的相对作用，我们进行了两个额外的系列实验。为了测试限制时间的效果，但不是Shh产生的量，我们在肢体发育的各个阶段用刺猬拮抗剂环巴宁处理鸡胚。我们发现，短时间暴露于嘘的结果，在规格的最前面的数字和更多的后面的数字指定顺序增加的时间不间断的嘘活动。为了测试限制产生的Shh水平而不是暴露时间的效果，我们对小鼠的Shh产生进行了遗传修饰。如前所示，降低所产生的Sbh浓度和Shh暴露的持续时间会导致后位数字的丢失。我们发现，在整个正常的时间范围内保持低水平的Shh生产的ZPA信号的结果在一个接近完全恢复的最后的数字。这些数据是一致的，并提供额外的支持，该模型的浓度的Shh看到和持续时间的曝光都有助于剂量依赖性规格的数字身份，但对于最后的数字的时间组件是更关键的参数。(c)2007爱思唯尔公司All rights reserved.
Sonic hedgehog (Shh) is a key signal in establishing different digit fates along the anterior-posterior axis of the vertebrate limb bud. Although the anterior digits appear to be specified by differential concentrations of Shh in a traditional, morphogen-like response, recent studies have suggested that posterior digits are specified by an extended time of exposure to Shh rather than, or in addition to, a threshold concentration of Shh. This model for digit patterning depends upon continued Shh signaling in the posterior limb through mid-to-late bud stages. We find that cyclopamine, a potent antagonist of Shh signaling, can down-regulate hedgehog target genes in the posterior limb throughout the time Shh is expressed, indicating that continued active Shh signaling indeed takes place. To further explore the relative roles of time and concentration of Shh during limb development, we carried out two additional series of experiments. To test the effect of limiting the time, but not the amount of Shh produced, we treated chick embryos with the hedgehog antagonist cycloparnine at various stages of limb development. We find that short exposures to Shh result in specification of only the most anterior digits and that more posterior digits are specified sequentially with increasing times of uninterrupted Shh activity. To test the effect of limiting the level of Shh produced, but not the time of exposure, we genetically modified Shh production in mice. As previously shown, reducing both the concentration of Sbh produced and the duration of Shh exposure results in a loss of posterior digits. We find that maintaining a low level of Shh production throughout the normal time frame of ZPA signaling results in a near complete restoration of the posterior-most digits. These data are consistent with, and lend additional support to, the model that concentration of Shh seen and duration of exposure both contribute to the dose-dependent specification of digit identities, but for the posterior-most digits the temporal component is the more critical parameter. (c) 2007 Elsevier Inc. All rights reserved.