Development of mammalian lung involves reiterative outgrowth and branching of an epithelial tube into the surrounding mesenchymal bed. Each coordinated growth and branching cycle is driven by reciprocal signalling between epithelial and adjacent mesenchymal cells. This signalling network includes FGF, SHH, BMP4 and other pathways. We have characterized lung defects in 36Pub mice carrying a deletion that removes an antagonist of FGF signalling, Spry2. Spry2 deficient mice show an enlarged cystic structure located in the terminus of each lobes. Our study shows that Spry2 deficient lungs have reduced lung branching and the cystic structure forms in the early lung development stage. Furthermore, mice carrying a targeted disruption of Spry2 fail to complement the lung phenotype characterized in 36Pub mice. A Spry2-BAC transgene rescues the defect. Interestingly, cystic structure growth is accompanied by the reduced and spatially disorganized expression of Fgf10 and elevated expression of Shh and Bmp4. Altered signalling balance due to the loss of Spry2 causes a delayed branch cycle and cystic growth. Our data underscores the importance of restricting cellular responsiveness to signalling and highlights the interplay between morphogenesis events and spatial localization of gene expression.

中文翻译：

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Spry2在肺发育过程中调节信号动力学和末端芽分支行为。

哺乳动物肺的发育涉及可再生的向外生长和上皮管分支进入周围的间充质床。每个协调的生长和分支周期是由上皮细胞和相邻的间充质细胞之间的相互信号驱动的。该信号网络包括FGF，SHH，BMP4和其他途径。我们已经表征了携带缺失的36Pub小鼠的肺部缺陷，该缺失可以去除FGF信号拮抗剂Spry2。Spry2缺陷小鼠在每个肺叶的末端均显示出增大的囊性结构。我们的研究表明，Spry2缺陷型肺在肺发育的早期阶段减少了肺分支，并形成了囊性结构。此外，携带Spry2靶向破坏的小鼠无法补充36Pub小鼠的肺表型。Spry2-BAC转基因可以挽救该缺陷。有趣的是，囊性结构的生长伴随着Fgf10表达的减少和空间混乱以及Shh和Bmp4的表达升高。由于Spry2丢失而引起的信号平衡改变，导致延迟的分支周期和囊性生长。我们的数据强调了限制细胞对信号传导的反应的重要性，并强调了形态发生事件与基因表达的空间定位之间的相互作用。