Levels of mesenchymal FGFR2 signaling modulate smooth muscle progenitor cell commitment in the lung
Levels of mesenchymal FGFR2 signaling modulate smooth muscle progenitor cell commitment in the lung
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DOI：
10.1016/j.ydbio.2006.07.001
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发表时间：
2006-11-01
影响因子：
2.7
通讯作者：
Bellusci, Saverio
中科院分区：
文献类型：
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作者：
De langhe, Stijn P.;Carraro, Gianni;Bellusci, Saverio
成纤维细胞生长因子（FGF）信号已被证明可调节肺上皮发育，但其对间充质分化的影响研究甚少。为了研究间充质中FGF信号在间充质分化中的作用及其对上皮形态发生的影响，我们利用了Fgfr2c(+/Δ)小鼠，由于剪接转换，这些小鼠在间充质组织中表达Fgfr2b，并表现出Apert综合征样表型。通过一系列体内和体外研究，我们表明在突变的肺间充质中建立了一个自分泌的FGF10 - FGFR2b信号环路，这产生了若干后果。它阻止平滑肌祖细胞进入平滑肌细胞（SMC）谱系，并导致纤连蛋白和弹性蛋白沉积减少。突变间充质自身内Fgf10的表达水平升高。上皮分支以及上皮中FGF和经典Wnt信号水平显著降低。这些缺陷导致终末气道发育停滞以及出生后肺部出现“肺气肿样”表型。我们的工作揭示了控制正常肺发育的部分复杂相互作用，可能与理解Apert综合征中呼吸缺陷的基础有关。（c）2006 Elsevier Inc.保留所有权利。
Fibroblast growth factor (FGF) signaling has been shown to regulate lung epithelial development but its influence on mesenchymal differentiation has been poorly investigated. To study the role of mesenchymal FGF signaling in the differentiation of the mesenchyme and its impact on epithelial morphogenesis, we took advantage of Fgfr2c(+/Delta) mice, which due to a splicing switch express Fgfr2b in mesenchymal tissues and manifest Apert syndrome-like phenotypes. Using a set of in vivo and in vitro studies, we show that an autocrine FGF10-FGFR2b signaling loop is established in the mutant lung mesenchyme, which has several consequences. It prevents the entry of the smooth muscle progenitors into the smooth muscle cell (SMC) lineage and results in reduced fibronectin and elastin deposition. Levels of Fgf10 expression are raised within the mutant mesenchyme itself. Epithelial branching as well as epithelia] levels of FGF and canonical Wnt signaling is dramatically reduced. These defects result in arrested development of terminal airways and an "emphysema like" phenotype in postnatal lungs. Our work unravels part of the complex interactions that govern normal lung development and may be pertinent to understanding the basis of respiratory defects in Apert syndrome. (c) 2006 Elsevier Inc. All rights reserved.