Follistatin-like 1 (Fstl1) is a bone morphogenetic protein (BMP) 4 signaling antagonist in controlling mouse lung development
Follistatin-like 1 (Fstl1) is a bone morphogenetic protein (BMP) 4 signaling antagonist in controlling mouse lung development
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Follistatin-like 1 (Fstl1) 是一种骨形态发生蛋白 (BMP) 4 信号拮抗剂，可控制小鼠肺部发育
DOI：
10.1073/pnas.1007293108
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发表时间：
2011-04-26
影响因子：
11.1
通讯作者：
Ning, Wen
中科院分区：
文献类型：
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作者：
Geng, Yan;Dong, Yingying;Ning, Wen
肺形态发生是一个精心策划的，通过几个分子途径，包括TGF-β/骨形态发生蛋白（BMP）信号转导的严格调控的过程。这些信号通路的改变导致肺畸形。我们研究了卵泡抑素样1（Fstl 1），一种分泌的含卵泡抑素模块的糖蛋白，在肺发育中的作用。小鼠Fstl 1缺失导致出生后呼吸衰竭致死。突变表型的分析表明，Fstl 1是气管软骨形成和肺泡成熟所必需的。Fstl 1基因的缺失导致畸形的气管环表现为中断的环和环数量减少。fstl 1基因缺陷小鼠表现为间隔细胞过多和呼气末肺不张，这与远端肺泡上皮细胞分化受损和成熟表面活性蛋白产生不足有关。在机制上，Fstl 1直接与BMP 4相互作用，负调节BMP 4/Smad 1/5/8信号传导，并抑制BMP 4诱导的表面活性剂基因表达。通过Noggin降低BMP信号传导活性挽救了Fstl 1缺陷小鼠的肺不张。因此，我们提供了体内和体外的证据，证明Fstl 1调节肺发育和肺泡成熟，部分，通过BMP 4信号。
Lung morphogenesis is a well orchestrated, tightly regulated process through several molecular pathways, including TGF-beta/bone morphogenetic protein (BMP) signaling. Alteration of these signaling pathways leads to lung malformation. We investigated the role of Follistatin-like 1 (Fstl1), a secreted follistatin-module-containing glycoprotein, in lung development. Deletion of Fstl1 in mice led to postnatal lethality as a result of respiratory failure. Analysis of the mutant phenotype showed that Fstl1 is essential for tracheal cartilage formation and alveolar maturation. Deletion of the Fstl1 gene resulted in malformed tracheal rings manifested as discontinued rings and reduced ring number. Fstl1-deficient mice displayed septal hypercellularity and end-expiratory atelectasis, which were associated with impaired differentiation of distal alveolar epithelial cells and insufficient production of mature surfactant proteins. Mechanistically, Fstl1 interacted directly with BMP4, negatively regulated BMP4/Smad1/5/8 signaling, and inhibited BMP4-induced surfactant gene expression. Reducing BMP signaling activity by Noggin rescued pulmonary atelectasis of Fstl1-deficient mice. Therefore, we provide in vivo and in vitro evidence to demonstrate that Fstl1 modulates lung development and alveolar maturation, in part, through BMP4 signaling.