A Hox-Wnt-Sox signaling axis regulates lung development, patterning and branching

描述（由申请人提供）：该提案基于两个新发现，确定Sox9和Hox5在肺发育中起关键作用。除了发现这些转录因子在早期肺模式和分支形态发生中的新作用外，我们的初步证据表明，Hox5调节间质中Wnt信号传导，以控制间质和上皮中Sox9表达上游的间质-上皮串音。通过确定Hox5和Sox9调节肺发育的新分子机制，这项工作将为我们对肺器官发生的现有理解增加重要的新数据。此外，所提出的实验旨在综合综合Sox9和Hox5如何与Wnt/ -catenin信号通路整合，以调节肺发育的早期事件，包括模式，分支形态发生，增殖和分化。为了充分阐明这种新的Hox-Wnt-Sox信号轴，我们将定义Hox5和Sox9介导的肺发育分子调控，并确定Hox5通过调节Wnt/ -catenin信号来控制间质-上皮串音和Sox9表达的机制。

DESCRIPTION (provided by applicant): This proposal is based on two novel findings that identify both Sox9 and Hox5 as critical players in lung development. In addition to identifying novel roles for these transcription factors in early lung patterning and branching morphogenesis, our preliminary evidence suggests that Hox5 regulates Wnt signaling in the mesenchyme to control mesenchyme-epithelial crosstalk upstream of Sox9 expression in both the mesenchyme and epithelium. By identifying novel molecular mechanisms by which Hox5 and Sox9 regulate lung development, the proposed work will add significant new data to our existing understanding of lung organogenesis. Furthermore, the proposed experiments are designed to synthesize a comprehensive view of how Sox9 and Hox5 integrate with the Wnt/�-catenin signaling pathway to regulate early events in lung development, including patterning, branching morphogenesis, proliferation and differentiation. In order to fully elucidate this novel Hox-Wnt-Sox signaling axi, we will define Hox5- and Sox9-mediated molecular regulation of lung development and determine the mechanisms by which Hox5 modulates Wnt/�-catenin signaling to control mesenchymal-epithelial crosstalk and Sox9 expression.