Mesodermal Deletion of Transforming Growth Factor-β Receptor II Disrupts Lung Epithelial Morphogenesis CROSS-TALK BETWEEN TGF-β AND SONIC HEDGEHOG PATHWAYS
Mesodermal Deletion of Transforming Growth Factor-β Receptor II Disrupts Lung Epithelial Morphogenesis CROSS-TALK BETWEEN TGF-β AND SONIC HEDGEHOG PATHWAYS
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DOI：
10.1074/jbc.m806786200
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发表时间：
2008-12-26
影响因子：
4.8
通讯作者：
Minoo, Parviz
中科院分区：
文献类型：
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作者：
Li, Min;Li, Changgong;Minoo, Parviz
在脊椎动物中，Sonic hedgehog（Shh）和转化生长因子-β（TGF-β）信号通路在许多形态发生过程中以重叠的方式发生。体外数据表明，这两种途径可能相互作用。这种相互作用是否发生在胚胎发育过程中仍不清楚。使用胚胎肺形态发生作为模型，我们产生了转基因小鼠，其中编码II型TGF-β受体的T β RII基因的外显子2通过中胚层特异性Cre被删除。中胚层特异性T β RII缺失（T β RII Delta/Delta）导致胚胎死亡。肺内气管、支气管软骨数量和形态异常。在肺实质中，上皮-间充质相互作用对正常发育至关重要，间充质T β RII的缺失导致上皮形态发生异常。T β RII Delta/Delta肺中正常上皮分支形态发生的失败导致囊性气道畸形。肺间质中T β RII位点的中断增加了Patched和Gli-1的mRNA，这两个Shh信号传导的下游靶点，而不改变上皮中产生的Shh配体水平。因此，我们得出结论，T β RII介导的信号在肺间充质调节转导的Shh信号来源于上皮细胞。据我们所知，这是在胚胎发育过程中Shh和TGF-β通路之间相互和新的交叉通信模式的第一个体内证据。
In vertebrates, Sonic hedgehog (Shh) and transforming growth factor-beta(TGF-beta) signaling pathways occur in an overlapping manner in many morphogenetic processes. In vitro data indicate that the two pathways may interact. Whether such interactions occur during embryonic development remains unknown. Using embryonic lung morphogenesis as a model, we generated transgenic mice in which exon 2 of the T beta RII gene, which encodes the type II TGF-beta receptor, was deleted via a mesodermal-specific Cre. Mesodermal-specific deletion of T beta RII (T beta RII Delta/Delta) resulted in embryonic lethality. The lungs showed abnormalities in both number and shape of cartilage in trachea and bronchi. In the lung parenchyma, where epithelial-mesenchymal interactions are critical for normal development, deletion of mesenchymal T beta RII caused abnormalities in epithelial morphogenesis. Failure in normal epithelial branching morphogenesis in the T beta RII Delta/Delta lungs caused cystic airway malformations. Interruption of the T beta RII locus in the lung mesenchyme increased mRNA for Patched and Gli-1, two downstream targets of Shh signaling, without alterations in Shh ligand levels produced in the epithelium. Therefore, we conclude that T beta RII-mediated signaling in the lung mesenchyme modulates transduction of Shh signaling that originates from the epithelium. To our knowledge, this is the first in vivo evidence for a reciprocal and novel mode of cross-communication between Shh and TGF-beta pathways during embryonic development.