Sox9 plays multiple roles in the lung epithelium during branching morphogenesis
Sox9 plays multiple roles in the lung epithelium during branching morphogenesis
复制标题
DOI：
10.1073/pnas.1311847110
复制
发表时间：
2013-11-19
影响因子：
11.1
通讯作者：
Spence, Jason R.
中科院分区：
文献类型：
--
作者：
Rockich, Briana E.;Hrycaj, Steven M.;Spence, Jason R.
肺分支形态发生是一个高度协调的过程，在成人肺中产生复杂的气体交换单位网络。信号通路、转录因子和上皮-间充质串扰的复杂调节对于确保分支形态发生正确发生至关重要。在这里，我们描述了转录因子Sox 9在肺分支形态发生过程中的作用。Sox 9在分支上皮的远端以高度动态的方式表达，并在胚胎第16.5天开始下调，同时发生1型和2型肺泡细胞的终末分化。使用上皮特异性遗传功能丧失和获得的方法，我们的研究结果表明，Sox 9控制肺分支的多个方面。Sox 9水平的精细调节是平衡上皮尖端祖细胞的增殖和分化所必需的，并且Sox 9的缺失导致直接和间接的细胞缺陷，包括细胞外基质缺陷、细胞骨架解体和异常上皮运动。我们的证据表明，与其他内胚层来源的上皮组织（例如肠）不同，Wnt/β-连环蛋白信号传导不会调节肺中Sox 9的表达。我们的结论是，Sox 9共同促进适当的分支形态通过控制增殖和分化之间的平衡，调节细胞外基质。
Lung branching morphogenesis is a highly orchestrated process that gives rise to the complex network of gas-exchanging units in the adult lung. Intricate regulation of signaling pathways, transcription factors, and epithelial-mesenchymal cross-talk are critical to ensuring branching morphogenesis occurs properly. Here, we describe a role for the transcription factor Sox9 during lung branching morphogenesis. Sox9 is expressed at the distal tips of the branching epithelium in a highly dynamic manner as branching occurs and is down-regulated starting at embryonic day 16.5, concurrent with the onset of terminal differentiation of type 1 and type 2 alveolar cells. Using epithelial-specific genetic loss- and gain-of-function approaches, our results demonstrate that Sox9 controls multiple aspects of lung branching. Fine regulation of Sox9 levels is required to balance proliferation and differentiation of epithelial tip progenitor cells, and loss of Sox9 leads to direct and indirect cellular defects including extracellular matrix defects, cytoskeletal disorganization, and aberrant epithelial movement. Our evidence shows that unlike other endoderm-derived epithelial tissues, such as the intestine, Wnt/beta-catenin signaling does not regulate Sox9 expression in the lung. We conclude that Sox9 collectively promotes proper branching morphogenesis by controlling the balance between proliferation and differentiation and regulating the extracellular matrix.