Bellusci S, Grindley J, Emoto H, Itoh N, Hogan B L
Department of Cell Biology, Vanderbilt University Medical Center, Nashville, Tennessee 37232-2175, USA.
Development. 1997 Dec;124(23):4867-78. doi: 10.1242/dev.124.23.4867.
During mouse lung morphogenesis, the distal mesenchyme regulates the growth and branching of adjacent endoderm. We report here that fibroblast growth factor 10 (Fgf10) is expressed dynamically in the mesenchyme adjacent to the distal buds from the earliest stages of lung development. The temporal and spatial pattern of gene expression suggests that Fgf10 plays a role in directional outgrowth and possibly induction of epithelial buds, and that positive and negative regulators of Fgf10 are produced by the endoderm. In transgenic lungs overexpressing Shh in the endoderm, Fgf10 transcription is reduced, suggesting that high levels of SHH downregulate Fgf10. Addition of FGF10 to embryonic day 11.5 lung tissue (endoderm plus mesenchyme) in Matrigel or collagen gel culture elicits a cyst-like expansion of the endoderm after 24 hours. In Matrigel, but not collagen, this is followed by extensive budding after 48-60 hours. This response involves an increase in the rate of endodermal cell proliferation. The activity of FGF1, FGF7 and FGF10 was also tested directly on isolated endoderm in Matrigel culture. Under these conditions, FGF1 elicits immediate endodermal budding, while FGF7 and FGF10 initially induce expansion of the endoderm. However, within 24 hours, samples treated with FGF10 give rise to multiple buds, while FGF7-treated endoderm never progresses to bud formation, at all concentrations of factor tested. Although exogenous FGF1, FGF7 and FGF10 have overlapping activities in vitro, their in vivo expression patterns are quite distinct in relation to early branching events. We conclude that, during early lung development, localized sources of FGF10 in the mesoderm regulate endoderm proliferation and bud outgrowth.
在小鼠肺形态发生过程中，远端间充质调节相邻内胚层的生长和分支。我们在此报告，成纤维细胞生长因子10（Fgf10）从肺发育的最早阶段开始就在远端芽相邻的间充质中动态表达。基因表达的时空模式表明，Fgf10在定向生长以及可能诱导上皮芽方面发挥作用，并且内胚层产生Fgf10的正负调节因子。在内胚层中过表达Shh的转基因肺中，Fgf10转录减少，这表明高水平的SHH下调Fgf10。在基质胶或胶原凝胶培养中，将FGF10添加到胚胎第11.5天的肺组织（内胚层加间充质）中，24小时后内胚层会出现囊肿样扩张。在基质胶中，但不在胶原中，48 - 60小时后会出现广泛的出芽。这种反应涉及内胚层细胞增殖速率的增加。还在基质胶培养中直接测试了FGF1、FGF7和FGF10对分离的内胚层的活性。在这些条件下，FGF1立即引发内胚层出芽，而FGF7和FGF10最初诱导内胚层扩张。然而，在24小时内，用FGF10处理的样本会产生多个芽，而在所有测试因子浓度下，用FGF7处理的内胚层从未发展到芽形成阶段。尽管外源性FGF1、FGF7和FGF10在体外具有重叠活性，但它们在体内与早期分支事件相关的表达模式却截然不同。我们得出结论，在肺早期发育过程中，中胚层中FGF10的局部来源调节内胚层增殖和芽的生长。
