Spry2 regulates signalling dynamics and terminal bud branching behaviour during lung development.
Spry2 regulates signalling dynamics and terminal bud branching behaviour during lung development.
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Spry2 调节肺发育过程中的信号动力学和顶芽分支行为。
DOI：
10.1017/s0016672315000026
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发表时间：
2015
影响因子：
1.5
通讯作者：
O'Brien,TimothyP
中科院分区：
文献类型：
--
作者：
Zhao,Yingying;O'Brien,TimothyP
哺乳动物肺的发育涉及上皮管向周围间质床的反复生长和分支。每个协调的生长和分支周期都是由上皮细胞和相邻间充质细胞之间的相互信号传导驱动的。这个信号网络包括FGF、SHH、BMP4和其他途径。我们在36Pub小鼠的肺缺陷中发现了FGF信号拮抗剂Spry2的缺失。Spry2缺陷小鼠在每个脑叶末端显示一个增大的囊性结构。我们的研究表明，Spry2缺陷肺在肺发育早期出现肺分支减少和囊性结构形成。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转基因修复了这一缺陷。有趣的是，囊性结构的生长伴随着Fgf10的表达减少和空间紊乱，以及Shh和Bmp4的表达升高。由于Spry2缺失导致的信号平衡改变导致分支周期延迟和囊性生长。我们的数据强调了限制细胞对信号的反应的重要性，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。
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.