van Tuyl Minke, Liu Jason, Groenman Freek, Ridsdale Ross, Han Robin N N, Venkatesh Vikram, Tibboel Dick, Post Martin
Program in Lung Biology, Hospital for Sick Children Research Inst., Toronto, Ontario, Canada.
Am J Physiol Lung Cell Mol Physiol. 2006 Apr;290(4):L777-L789. doi: 10.1152/ajplung.00293.2005. Epub 2005 Nov 18.
Lung development is a highly regulated process directed by mesenchymal-epithelial interactions, which coordinate the temporal and spatial expression of multiple regulatory factors required for proper lung formation. The Iroquois homeobox (Irx) genes have been implicated in the patterning and specification of several Drosophila and vertebrate organs, including the heart. Herein, we investigated whether the Irx genes play a role in lung morphogenesis. We found that Irx1-3 and Irx5 expression was confined to the branching lung epithelium, whereas Irx4 was not expressed in the developing lung. Antisense knockdown of all pulmonary Irx genes together dramatically decreased distal branching morphogenesis and increased distention of the proximal tubules in vitro, which was accompanied by a reduction in surfactant protein C-positive epithelial cells and an increase in beta-tubulin IV and Clara cell secretory protein positive epithelial structures. Transmission electron microscopy confirmed the proximal phenotype of the epithelial structures. Furthermore, antisense Irx knockdown resulted in loss of lung mesenchyme and abnormal smooth muscle cell formation. Expression of fibroblast growth factors (FGF) 1, 7, and 10, FGF receptor 2, bone morphogenetic protein 4, and Sonic hedgehog (Shh) were not altered in lung explants treated with antisense Irx oligonucleotides. All four Irx genes were expressed in Shh- and Gli(2)-deficient murine lungs. Collectively, these results suggest that Irx genes are involved in the regulation of proximo-distal morphogenesis of the developing lung but are likely not linked to the FGF, BMP, or Shh signaling pathways.
肺发育是一个由间充质-上皮相互作用高度调控的过程，这种相互作用协调了肺正常形成所需的多种调控因子的时空表达。易洛魁同源框（Irx）基因已被证明与果蝇和脊椎动物的多个器官（包括心脏）的模式形成和特化有关。在此，我们研究了Irx基因是否在肺形态发生中发挥作用。我们发现Irx1-3和Irx5的表达局限于分支的肺上皮，而Irx4在发育中的肺中不表达。体外共同反义敲低所有肺Irx基因显著降低了远端分支形态发生，并增加了近端小管的扩张，同时伴有表面活性蛋白C阳性上皮细胞减少以及β-微管蛋白IV和克拉拉细胞分泌蛋白阳性上皮结构增加。透射电子显微镜证实了上皮结构的近端表型。此外，反义Irx敲低导致肺间充质丧失和平滑肌细胞形成异常。在用反义Irx寡核苷酸处理的肺外植体中，成纤维细胞生长因子（FGF）1、7和10、FGF受体2、骨形态发生蛋白4和音猬因子（Shh）的表达未发生改变。所有四个Irx基因在Shh和Gli(2)缺陷的小鼠肺中均有表达。总体而言，这些结果表明Irx基因参与了发育中肺的近-远侧形态发生调控，但可能与FGF、BMP或Shh信号通路无关。
