Follistatin-like 1 (Fstl1) is a bone morphogenetic protein (BMP) 4 signaling antagonist in controlling mouse lung development

被引:190
作者
Geng, Yan [2 ]
Dong, Yingying [2 ]
Yu, Mingyan [2 ]
Zhang, Long [1 ]
Yan, Xiaohua [1 ]
Sun, Jingxia [2 ]
Qiao, Long [2 ]
Geng, Huixia [2 ]
Nakajima, Masahiro [3 ]
Furuichi, Tatsuya [3 ]
Ikegawa, Shiro [3 ]
Gao, Xiang [2 ]
Chen, Ye-Guang [1 ]
Jiang, Dianhua [4 ]
Ning, Wen [2 ,5 ]
机构
[1] Tsinghua Univ, State Key Lab Biomembrane & Membrane Biotechnol, Sch Life Sci, Beijing 100084, Peoples R China
[2] Nanjing Univ, Model Anim Res Ctr, Nanjing 210061, Peoples R China
[3] RIKEN, Ctr Genom Med, Tokyo 1088639, Japan
[4] Duke Univ, Sch Med, Dept Med, Div Pulm Allergy & Crit Care Med, Durham, NC 27710 USA
[5] Nankai Univ, Coll Life Sci, Tianjin 300071, Peoples R China
基金
中国国家自然科学基金;
关键词
lung atelectasis; trachea formation; surfactant protein C; lung epithelial differentiation; BRANCHING MORPHOGENESIS; GENE-EXPRESSION; CELL-LINE; MICE; DIFFERENTIATION; MECHANISMS; ABROGATION; RECEPTOR; CULTURE;
D O I
10.1073/pnas.1007293108
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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.
引用
收藏
页码:7058 / 7063
页数:6
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