Sonic hedgehog regulates branching morphogenesis in the mammalian lung
Sonic hedgehog regulates branching morphogenesis in the mammalian lung
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DOI：
10.1016/s0960-9822(98)70446-4
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发表时间：
1998-09-24
期刊：
影响因子：
9.2
通讯作者：
McMahon, AP
中科院分区：
文献类型：
--
作者：
Pepicelli, CV;Lewis, PM;McMahon, AP
哺乳动物的肺像许多其他器官一样，通过上皮的分支形态发生发育而来[1]。发育始于前肠内胚层的两个腹侧芽向下方的脏壁中胚层的外突。随着芽的延伸，它们在精确、恒定的位置发出侧支，形成初级气道和每个肺的肺叶。二叉分支导致气道进一步延伸。移植研究已经证明了支气管间充质在诱导上皮分支方面的重要性，但上皮信号传导的重要性在很大程度上尚未得到研究。形态发生素音猬因子（Shh）在前肠内胚层中广泛表达，并且在发生分支的肺远端上皮中特异性上调[2]。Shh的异位表达会破坏分支并增加增殖，这表明局部Shh信号传导调节肺的发育[2]。我们在此报告，Shh对呼吸系统的发育至关重要。在Shh基因缺失的突变体中，我们发现气管和食管不能正确分离，并且由于初级肺芽形成后分支和生长失败，肺形成一个原始的囊。有趣的是，气道上皮的正常近 - 远端分化发生了，这表明Shh对于分化事件不是必需的。此外，Shh的几个间充质表达的下游靶基因的转录被消除。这些结果强调了上皮来源的Shh在调节肺分支形态发生中的重要性。
The mammalian lung, like many other organs, develops by branching morphogenesis of an epithelium [1]. Development initiates with evagination of two ventral buds of foregut endoderm into the underlying splanchnic mesoderm. As the buds extend, they send out lateral branches at precise, invariant positions, establishing the primary airways and the lobes of each lung. Dichotomous branching leads to further extension of the airways, Grafting studies have demonstrated the importance of bronchial mesenchyme in inducing epithelial branching, but the significance of epithelial signaling has largely been unstudied. The morphogen Sonic hedgehog (Shh) is widely expressed in the foregut endoderm and is specifically upregulated in the distal epithelium of the lung where branching is occurring [2]. Ectopic expression of Shh disrupts branching and increases proliferation, suggesting that local Shh signaling regulates lung development [2]. We report here that Shh is essential for development of the respiratory system, In Shh null mutants, we found that the trachea and esophagus do not separate properly and the lungs form a rudimentary sac due to failure of branching and growth after formation of the primary lung buds. Interestingly, normal proximo-distal differentiation of the airway epithelium occurred, indicating that Shh is not needed for differentiation events. In addition, the transcription of several mesenchymally expressed downstream targets of Shh is abolished. These results highlight the importance of epithelially derived Shh in regulating branching morphogenesis of the lung.