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首页> 外文期刊>Journal of developmental origins of health and disease >Molecular determinants of design optimality in cardiopulmonary systems: Sprouty2 coordinates airway and vascular branching programmes in mammalian lung development.
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Molecular determinants of design optimality in cardiopulmonary systems: Sprouty2 coordinates airway and vascular branching programmes in mammalian lung development.

机译：心肺系统设计最优性的分子决定因素：Sprouty2坐标哺乳动物肺发育中的气道和血管分支计划。

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Background: Sprouty2 (Spry2) acts as a central regulator of tubular growth and branch patterning in the developing mammalian lung by controlling both magnitude and duration of growth factor signalling. To determine if this protein coordinates airway and vascular growth factor signalling, we tested the hypothesis that Spry2 links the primary cue for airway outgrowth, fibroblast growth factor-10 (FGF-10), to genomic events underpinning the expression and release of vascular endothelial growth factor-A (VEGF-A). Methods & Results: Using primary fetal distal lung epithelial cells (FDLE) from rat, and immortalised human bronchial epithelial cells (16HBE14o-), we utilised various molecular techniques such as western blotting, real-time PCR, chromatin immunoprecipitation and electrophoretic mobility shif assay. We identified a nuclear sub-population of Spry2 which interacted with regions of the rat and human VEGF-A promoter spanning the hypoxia response element (HRE) and adjacent 3' sites. In FDLE cultured at the PO2 of the fetal lung, FGF-10 relieved the Spry2 interaction at the HRE region by promoting clearance of a 39kDa form and this was accompanied by histone-3 S10K14 phosphoacetylation, promoter de-methyla-tion, hypoxia inducible factor-1a activation and VEGF-A expression. This repressive characteristic of nuclear Spry2 was relieved in 16HBE14o- by shRNA knockdown, and stable expression of mutants (C218A; C221A) that do not interact with the VEGF-A promoter HRE region. Conclusions: We conclude that nuclear Spry2 acts as a molecular link which co-ordinates airway and vascular growth of the cardiopulmonary system. This identifies Spry2 as a molecular determinant of design optimality in the mammalian lung.
机译：背景：Sprouty2（Spry2）通过控制生长因子信号传导的两个级别和持续时间，作为哺乳动物肺部的管状生长和分支图案化的中央调节器。为了确定该蛋白质是否协调气道和血管生长因子信号传导，我们测试了Spry2将主要提示链接到气道过剩的成纤维细胞生长因子-10（FGF-10）的假设，以基因组事件进行血管内皮生长的表达和释放因子-A（VEGF-A）。方法和结果：采用大鼠的原发性胎儿远端肺上皮细胞（FUTLE），和永生化的人支气管上皮细胞（16HBE14O-），我们利用了各种分子技术，如蛋白质印迹，实时PCR，染色质免疫沉淀和电泳迁移率SCIF测定。我们鉴定了一种核亚群，其与大鼠和人类VEGF-A启动子的区域相互作用，遍布缺氧反应元素（HRE）和相邻的3'位点。在胎儿肺部PO2培养的udde中，FGF-10通过促进39KDA形式的间隙来缓解HRE区域的甜点2相互作用，并且这伴有组蛋白-3 S10K14磷酸乙酰化，启动子脱氧，缺氧诱导因子-1a激活和VEGF-A表达。核Spry2的这种抑制特性在16HBE14-通过shRNA敲低，突变体（C218a; c221a）的稳定表达，其与VEGF-a启动子Hre区域不相互作用。结论：我们得出结论，核Spry2作为辅导呼吸道和心肺系统血管生长的分子环节。这将SPRy2识别为哺乳动物肺中设计最优性的分子决定率。

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