Tsuji Mayoko, Morishima Masae, Shimizu Kazuhiko, Morikawa Shunichi, Heglind Mikael, Enerbäck Sven, Ezaki Taichi, Tamaoki Jun
First Department of Medicine, Tokyo Women's Medical University, Tokyo, Japan.
Department of Anatomy and Developmental Biology, Tokyo Women's Medical University, Tokyo, Japan.
Dev Growth Differ. 2017 Aug;59(6):501-514. doi: 10.1111/dgd.12368. Epub 2017 Jul 4.
FOXC2, a forkhead transcriptional factor, is a candidate gene for congenital heart diseases and lymphedema-distichiasis syndrome and yellow nail syndrome; however, there are no reports on Foxc2 and the development of the lung. We have identified lung abnormalities in Foxc2-knockout embryos during investigation of cardiac development. The aim of this study was to clarify the morphological characteristics during lung development using ICR-Foxc2 knockout lungs. Mutant fetuses at embryonic days 10.5-18.5 were obtained from mating of Foxc2 mice and then analyzed. Notably, Foxc2-knockout lungs appeared parenchymatous and much smaller than those of the wild-type littermates. In the Foxc2 knockout lungs, the capillary beds remained distant from the alveolar epithelium until the late stages, the number of type2 alveolar cells per alveolar progenitor cell was lower and the type1 alveolar cells were thicker in Foxc2 knockout mice. In contrast, Foxc2 expression was only detected in the mesenchyme of the lung buds at E10.5, and it disappeared at E11.5 in Foxc2-LacZ knockin mice. Furthermore, the expression of Lef1 was significantly inhibited in E11.5 lungs. All of these results suggest that the abnormalities in Foxc2 knockout mice may involve maldifferentiation of alveolar epithelial cells and capillary vessel endothelial-alveolar epithelial approach as well as lymph vessel malformation. This is the first report about relationship between Foxc2 and lung development. This animal model might provide an important clue for elucidating the mechanism of lung development and the cause of respiratory diseases.
叉头转录因子FOXC2是先天性心脏病、淋巴水肿-双行睫综合征和黄甲综合征的候选基因；然而，尚无关于Foxc2与肺发育的报道。在研究心脏发育过程中，我们在Foxc2基因敲除胚胎中发现了肺部异常。本研究的目的是利用ICR-Foxc2基因敲除小鼠的肺来阐明肺发育过程中的形态学特征。从Foxc2小鼠交配中获得胚胎第10.5 - 18.5天的突变胎儿，然后进行分析。值得注意的是，Foxc2基因敲除小鼠的肺呈现实质性，且比野生型同窝小鼠的肺小得多。在Foxc2基因敲除小鼠的肺中，直到晚期毛细血管床与肺泡上皮仍保持较远的距离，每个肺泡祖细胞的Ⅱ型肺泡细胞数量较少，且Ⅰ型肺泡细胞更厚。相比之下，在E10.5时仅在肺芽的间充质中检测到Foxc2表达，在Foxc2-LacZ基因敲入小鼠中E11.5时其表达消失。此外，E11.5肺中Lef1的表达受到显著抑制。所有这些结果表明，Foxc2基因敲除小鼠的异常可能涉及肺泡上皮细胞的分化异常、毛细血管内皮-肺泡上皮靠近异常以及淋巴管畸形。这是关于Foxc2与肺发育关系的首次报道。该动物模型可能为阐明肺发育机制和呼吸系统疾病病因提供重要线索。
