Developmental Biology and Regenerative Medicine Program, Saban Research Institute, Childrens Hospital Los Angeles, Keck School of Medicine of University of Southern California, 4650 Sunset Boulevard MS35, Los Angeles, CA 90027, USA.
Dev Biol. 2011 Feb 1;350(1):112-26. doi: 10.1016/j.ydbio.2010.11.022. Epub 2010 Dec 1.
The proper level of proliferation and differentiation along the proximodistal axis is crucial for lung organogenesis. Elucidation of the factors that control these processes will therefore provide important insights into embryonic lung development and regeneration. Eya1 is a transcription factor/protein phosphatase that regulates cell lineage specification and proliferation. Yet its functions during lung development are unknown. In this paper we show that Eya1(-/-) lungs are severely hypoplastic with reduced epithelial branching and increased mesenchymal cellularity. Eya1 is expressed at the distal epithelial tips of branching tubules as well as in the surrounding distal mesenchyme. Eya1(-/-) lung epithelial cells show loss of progenitor cell markers with increased expression of differentiation markers and cell cycle exit. In addition, Eya1(-/-) embryos and newborn mice exhibit severe defects in the smooth muscle component of the bronchi and major pulmonary vessels with decreased Fgf10 expression. These defects lead to rupture of the major vessels and hemorrhage into the lungs after birth. Treatment of Eya1(-/-) epithelial explants in culture with recombinant Fgf10 stimulates epithelial branching. Since Shh expression and activity are abnormally increased in Eya1(-/-) lungs, we tested whether genetically lowering Shh activity could rescue the Eya1(-/-) lung phenotype. Indeed, genetic reduction of Shh partially rescues Eya1(-/-) lung defects while restoring Fgf10 expression. This study provides the first evidence that Eya1 regulates Shh signaling in embryonic lung, thus ensuring the proper level of proliferation and differentiation along the proximodistal axis of epithelial, mesenchymal and endothelial cells. These findings uncover novel functions for Eya1 as a critical upstream coordinator of Shh-Fgf10 signaling during embryonic lung development. We conclude, therefore, that Eya1 function is critical for proper coordination of lung epithelial, mesenchymal and vascular development.
沿远近轴的适当增殖和分化水平对于肺发生至关重要。因此，阐明控制这些过程的因素将为胚胎肺发育和再生提供重要的见解。Eya1 是一种转录因子/蛋白磷酸酶，可调节细胞谱系特化和增殖。然而，它在肺发育过程中的功能尚不清楚。在本文中，我们表明 Eya1(-/-)肺严重发育不良，上皮分支减少，间充质细胞增多。Eya1 在分支小管的远端上皮尖端以及周围的远端间充质中表达。Eya1(-/-)肺上皮细胞显示祖细胞标志物丢失，分化标志物表达增加和细胞周期退出。此外，Eya1(-/-)胚胎和新生小鼠在支气管和主要肺血管的平滑肌成分中表现出严重缺陷，Fgf10 表达减少。这些缺陷导致出生后主要血管破裂和出血进入肺部。用重组 Fgf10 处理 Eya1(-/-)上皮外植体在培养中刺激上皮分支。由于 Eya1(-/-)肺中 Shh 表达和活性异常增加，我们测试了降低 Shh 活性是否可以挽救 Eya1(-/-)肺表型。事实上，Shh 活性的遗传降低部分挽救了 Eya1(-/-)肺缺陷，同时恢复了 Fgf10 的表达。这项研究首次证明 Eya1 调节胚胎肺中的 Shh 信号传导，从而确保上皮、间充质和内皮细胞沿远近轴的适当增殖和分化水平。这些发现揭示了 Eya1 作为胚胎肺发育过程中 Shh-Fgf10 信号传导的关键上游协调因子的新功能。因此，我们得出结论，Eya1 功能对于肺上皮、间充质和血管发育的适当协调至关重要。
