title: Follistatin-like 1 (Fstl1) is a bone morphogenetic protein (BMP) 4 signaling antagonist in controlling mouse lung development.
abstract: Lung morphogenesis is a well orchestrated, tightly regulated process through several molecular pathways, including TGF-β/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.
authors.affiliation: Model Animal Research Center, Nanjing University, Nanjing 210061, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Geng
authors.forename: Yingying
authors.initials: Y
authors.lastname: Dong
authors.forename: Mingyan
authors.initials: M
authors.lastname: Yu
authors.forename: Long
authors.initials: L
authors.lastname: Zhang
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Yan
authors.forename: Jingxia
authors.initials: J
authors.lastname: Sun
authors.forename: Long
authors.initials: L
authors.lastname: Qiao
authors.forename: Huixia
authors.initials: H
authors.lastname: Geng
authors.forename: Masahiro
authors.initials: M
authors.lastname: Nakajima
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Furuichi
authors.forename: Shiro
authors.initials: S
authors.lastname: Ikegawa
authors.forename: Xiang
authors.initials: X
authors.lastname: Gao
authors.forename: Ye-Guang
authors.initials: YG
authors.lastname: Chen
authors.forename: Dianhua
authors.initials: D
authors.lastname: Jiang
authors.forename: Wen
authors.initials: W
authors.lastname: Ning
mesh_terms: D000818:Animals; D055415:Bone Morphogenetic Protein 4 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002356:Cartilage / Q000166:cytology / Q000196:embryology; D045744:Cell Line, Tumor; D038702:Follistatin-Related Proteins / Q000235:genetics / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental / Q000502:physiology; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D011650:Pulmonary Alveoli / Q000166:cytology / Q000196:embryology*; D011663:Pulmonary Surfactants / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D051785:Smad Proteins / Q000235:genetics / Q000378:metabolism; D014132:Trachea / Q000166:cytology / Q000196:embryology; D000099176:Noggin Protein
chemical_list: D055415:Bone Morphogenetic Protein 4; D002352:Carrier Proteins; D038702:Follistatin-Related Proteins; D011663:Pulmonary Surfactants; D051785:Smad Proteins; D000099176:Noggin Protein; C525810:Bmp4 protein, mouse; C448720:Fstl1 protein, mouse