Shu Weiguo, Guttentag Susan, Wang Zhishan, Andl Thomas, Ballard Philip, Lu Min Min, Piccolo Stefano, Birchmeier Walter, Whitsett Jeffrey A, Millar Sarah E, Morrisey Edward E
Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Dev Biol. 2005 Jul 1;283(1):226-39. doi: 10.1016/j.ydbio.2005.04.014.
Branching morphogenesis in the lung serves as a model for the complex patterning that is reiterated in multiple organs throughout development. Beta-catenin and Wnt signaling mediate critical functions in cell fate specification and differentiation, but specific functions during branching morphogenesis have remained unclear. Here, we show that Wnt/beta-catenin signaling regulates proximal-distal differentiation of airway epithelium. Inhibition of Wnt/beta-catenin signaling, either by expression of Dkk1 or by tissue-specific deletion of beta-catenin, results in disruption of distal airway development and expansion of proximal airways. Wnt/beta-catenin functions upstream of BMP4, FGF signaling, and N-myc. Moreover, we show that beta-catenin and LEF/TCF activate the promoters of BMP4 and N-myc. Thus, Wnt/beta-catenin signaling is a critical upstream regulator of proximal-distal patterning in the lung, in part, through regulation of N-myc, BMP4, and FGF signaling.
肺中的分支形态发生是整个发育过程中多个器官反复出现的复杂模式形成的模型。β-连环蛋白和Wnt信号传导在细胞命运决定和分化中发挥关键作用，但在分支形态发生过程中的具体功能仍不清楚。在这里，我们表明Wnt/β-连环蛋白信号传导调节气道上皮的近端-远端分化。通过表达Dkk1或组织特异性缺失β-连环蛋白来抑制Wnt/β-连环蛋白信号传导，会导致远端气道发育中断和近端气道扩张。Wnt/β-连环蛋白在BMP4、FGF信号传导和N-myc的上游起作用。此外，我们表明β-连环蛋白和LEF/TCF激活BMP4和N-myc的启动子。因此，Wnt/β-连环蛋白信号传导是肺中近端-远端模式形成的关键上游调节因子，部分是通过调节N-myc、BMP4和FGF信号传导来实现的。
