Bmp4 and Fgf10 play opposing roles during lung bud morphogenesis.
Bmp4 and Fgf10 play opposing roles during lung bud morphogenesis.
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DOI：
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发表时间：
2000-06
期刊：
影响因子：
4.6
通讯作者：
M. Weaver;N. R. Dunn;B. Hogan
中科院分区：
文献类型：
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作者：
M. Weaver;N. R. Dunn;B. Hogan
小鼠肺的形态发生涉及上皮内胚层和周围间充质之间的相互作用，导致形成呼吸树基础的不变的早期分支模式。有证据表明，成纤维细胞生长因子10（Fgf 10）和骨形态发生蛋白4（Bmp 4），分别在远端间充质和内胚层中表达，在分支形态发生中发挥重要作用。为了更详细地研究这些作用，我们开发了一种体外培养系统，其中将分离的内胚层在具有负载Fgf的珠的Matrigel（TM）基质中孵育。此外，我们使用了Bmp 4（lacZ）系小鼠，其中lacZ忠实地报告Bmp 4表达。肺内胚层在体内的分析表明，Bmp 4（lacZ）的表达在芽生长，延伸和分支的动态模式。在体外，Fgf 10诱导分离的内胚层的增殖和趋化性，无论它是来自远端或近端肺。此外，48小时后，Bmp 4（lacZ）表达在最接近珠的内胚层中上调。向培养基中加入30-50 ng/ml的外源性纯化的Bmp 4抑制Fgf诱导的出芽或趋化性，并抑制总体增殖。相比之下，BMP结合蛋白头蛋白增强FGF诱导的形态发生。基于这些和其他结果，我们提出了一个模型的组合作用FGF 10和BMP 4在分支形态发生的肺。
Morphogenesis of the mouse lung involves reciprocal interactions between the epithelial endoderm and the surrounding mesenchyme, leading to an invariant early pattern of branching that forms the basis of the respiratory tree. There is evidence that Fibroblast growth factor 10 (Fgf10) and Bone Morphogenetic Protein 4 (Bmp4), expressed in the distal mesenchyme and endoderm, respectively, play important roles in branching morphogenesis. To examine these roles in more detail, we have exploited an in vitro culture system in which isolated endoderm is incubated in Matrigel(TM) substratum with Fgf-loaded beads. In addition, we have used a Bmp4(lacZ) line of mice in which lacZ faithfully reports Bmp4 expression. Analysis of lung endoderm in vivo shows a dynamic pattern of Bmp4(lacZ) expression during bud outgrowth, extension and branching. In vitro, Fgf10 induces both proliferation and chemotaxis of isolated endoderm, whether it is derived from the distal or proximal lung. Moreover, after 48 hours, Bmp4(lacZ) expression is upregulated in the endoderm closest to the bead. Addition of 30-50 ng/ml of exogenous purified Bmp4 to the culture medium inhibits Fgf-induced budding or chemotaxis, and inhibits overall proliferation. By contrast, the Bmp-binding protein Noggin enhances Fgf-induced morphogenesis. Based on these and other results, we propose a model for the combinatorial roles of Fgf10 and Bmp4 in branching morphogenesis of the lung.