Lu M M, Yang H, Zhang L, Shu W, Blair D G, Morrisey E E
Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Dev Dyn. 2001 Dec;222(4):667-80. doi: 10.1002/dvdy.1231.
The proximal-distal patterning of lung epithelium involves a complex series of signaling and transcriptional events resulting in the programmed differentiation of highly specialized cells for gas exchange and surfactant protein expression essential for postnatal lung function. The BMP signaling pathway has been shown to regulate cellular differentiation in the lung as well as other tissues. In this report, we show that the can family of related BMP antagonists, including gremlin, cer-1, PRDC, and Dan are expressed in the lung during embryonic development with gremlin expression observed in the proximal airway epithelium. The role of gremlin in lung development was explored by overexpressing it in the distal lung epithelium of transgenic mice using the human SP-C promoter. SP-C/gremlin transgenic mice exhibited a disruption of the proximal-distal patterning found in the airways of the mammalian lung. Expanded expression of the proximal epithelial cell markers CC10 and HFH-4 (Foxj1) was observed in the distal regions of transgenic lungs. Furthermore, smooth muscle alpha-actin expression was observed surrounding the distal airways of SP-C/gremlin mice, indicating a proximalization of distal lung tubules. These data suggest that gremlin plays an important role in lung morphogenesis by regulating the proximal-distal patterning of the lung during development.
肺上皮的近-远模式涉及一系列复杂的信号传导和转录事件，这些事件导致高度特化的细胞进行程序性分化，以实现气体交换和产生对出生后肺功能至关重要的表面活性蛋白。已证明骨形态发生蛋白（BMP）信号通路可调节肺以及其他组织中的细胞分化。在本报告中，我们表明，包括gremlin、cer-1、PRDC和Dan在内的相关BMP拮抗剂的can家族在胚胎发育期间在肺中表达，在近端气道上皮中观察到gremlin的表达。利用人SP-C启动子在转基因小鼠的远端肺上皮中过表达gremlin，以探究其在肺发育中的作用。SP-C/gremlin转基因小鼠表现出哺乳动物肺气道中近-远模式的破坏。在转基因肺的远端区域观察到近端上皮细胞标志物CC10和HFH-4（Foxj1）的表达增加。此外，在SP-C/gremlin小鼠的远端气道周围观察到平滑肌α-肌动蛋白的表达，表明远端肺小管出现近端化。这些数据表明，gremlin在发育过程中通过调节肺的近-远模式在肺形态发生中起重要作用。
