Manifestation of the limb prepattern: Limb development in the absence of sonic hedgehog function
Manifestation of the limb prepattern: Limb development in the absence of sonic hedgehog function
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DOI：
10.1006/dbio.2001.0346
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发表时间：
2001-08-15
影响因子：
2.7
通讯作者：
Fallon, JF
中科院分区：
文献类型：
--
作者：
Chiang, C;Litingtung, Y;Fallon, JF
由Sonic hedgehog（Shh）基因编码的分泌蛋白定位于脊椎动物肢芽的后缘，并且被认为是建立前后肢极性的关键信号。在Shh（-/-）突变小鼠中，许多胚胎结构（包括肢体）的发育严重受损。在这项研究中，我们详细报告了Shh（-/-）突变肢体的分析。每个突变胚胎都有四肢，可识别的肱骨/股骨具有前后极性。在手肘/膝关节的远端，骨骼元素代表了zeugopod的形式，但缺乏可识别的前后极性。因此，Shh在小鼠肢体发育过程中，在茎足/zeugopod连接处或其远端（肘/膝关节）的正常肢体发育中特别必要。前肢足由单个远端软骨元件代表，而后肢足总是由单个足趾组成，具有成形良好的指间关节和终节趾骨处的背甲床。GDF 5和Hoxd 11 -13在后肢直足动物中的表达分析表明，形成的数字具有数字1的身份。这一发现被证实的形成只有两个趾骨元素，这是唯一的第一趾的脚。在形态相对正常的Shh（-/-）突变体芽中诱导出顶端外胚层嵴（AER）。我们报告说，随着发育时间的推移，Shh（-/-）AER的结构逐渐被破坏，同时嵴中Fgf 8的表达减少。同时，Shh（-/-）肢芽中的异常细胞死亡发生在前肢和后肢的前间充质中。值得注意的是，AER的变化和中胚层细胞死亡发生在Shh（-/-）前肢比后肢芽早。这提供了一个解释的后肢特异性的能力，形成autopodial结构的突变体。最后，与野生型小鼠肢芽不同，Shh（-/-）突变体后肢芽中胚层在移植到鸡肢芽的前边缘时不会引起手指重复，因此缺乏极化活性。我们建议，一个预模式存在于肢体领域的三个轴新兴的肢体芽以及特定的肢体骨骼元素。根据这个模型，肢芽信号中心，包括通过Shh起作用的极化活动区（ZPA），需要详细说明由原生肢场预模式提供的轴向信息。(C)北京：科学出版社.
The secreted protein encoded by the Sonic hedgehog (Shh) gene is localized to the posterior margin of vertebrate limb buds and is thought to be a key signal in establishing anterior-posterior limb polarity. In the Shh(-/-) mutant mouse, the development of many embryonic structures, including the limb, is severely compromised. in this study, we report the analysis of Shh(-/-) mutant limbs in detail. Each mutant embryo has four limbs with recognizable humerus/femur bones that have anterior-posterior polarity. Distal to the elbow/knee joints, skeletal elements representing the zeugopod form but lack identifiable anterior-posterior polarity. Therefore, Shh specifically becomes necessary for normal limb development at or just distal to the stylopod/zeugopod junction (elbow/knee joints) during mouse limb development. The forelimb autopod is represented by a single distal cartilage element, while the hindlimb autopod is invariably composed of a single digit with well-formed interphalangeal joints and a dorsal nail bed at the terminal phalanx. Analysis of GDF5 and Hoxd11-13 expression in the hindlimb autopod suggests that the forming digit has a digit-one identity. This finding is corroborated by the formation of only two phalangeal elements which are unique to digit one on the foot. The apical ectodermal ridge (AER) is induced in the Shh(-/-) mutant buds with relatively normal morphology. We report that the architecture of the Shh(-/-) AER is gradually disrupted over developmental time in parallel with a reduction of Fgf8 expression in the ridge. Concomitantly, abnormal cell death in the Shh(-/-) limb bud occurs in the anterior mesenchyme of both fore- and hindlimb. It is notable that the AER changes and mesodermal cell death occur earlier in the Shh(-/-) forelimb than the hindlimb bud. This provides an explanation for the hindlimb-specific competence to form autopodial structures in the mutant. Finally, unlike the wild-type mouse limb bud, the Shh(-/-) mutant posterior limb bud mesoderm does not cause digit duplications when grafted to the anterior border of chick limb buds, and therefore lacks polarizing activity. We propose that a prepattern exists in the limb field for the three axes of the emerging limb bud as well as specific limb skeletal elements. According to this model, the limb bud signaling centers, including the zone of polarizing activity (ZPA) acting through Shh, are required to elaborate upon the axial information provided by the native limb field prepattern. (C) 2001 Academic Press.