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(BMP) 4 Signaling Antagonist in Controlling Mouse Lung Development

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(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 Yan Genga,1, Yingying Donga,1, Mingyan Yua,1, Long Zhangb, Xiaohua Yanb, Jingxia Suna, Long Qiaoa, Huixia Genga, Masahiro Nakajimac, Tatsuya Furuichic, Shiro Ikegawac, Xiang Gaoa, Ye-Guang Chenb,2, Dianhua Jiangd,2, and Wen Ninga,e,2 aModel Animal Research Center, Nanjing University, Nanjing 210061, China; bState Key Laboratory of Biomembrane and Membrane Biotechnology, School of Life Sciences, Tsinghua University, Beijing 100084, China; cCenter for Genomic Medicine, RIKEN, Tokyo 108-8639, Japan; dDepartment of Medicine, Division of Pulmonary, Allergy, and Critical Care Medicine, Duke University School of Medicine, Durham, NC 27710; and eCollege of Life Sciences, Nankai University, Tianjin 300071, China Edited by Gail Martin, University of California, San Francisco, CA, and approved March 7, 2011 (received for review June 18, 2010) Lung morphogenesis is a well orchestrated, tightly regulated BMP4 gain of function in the lung results in less extensive process through several molecular pathways, including TGF-β/bone branching and decreased distal epithelial differentiation (11). morphogenetic protein (BMP) signaling. Alteration of these signal- The precise mechanism of TGF-β family members in regulating ing pathways leads to lung malformation. We investigated the role lung development is largely unclear. of Follistatin-like 1 (Fstl1), a secreted follistatin-module–containing Follistatin-like 1 (Fstl1), first identified as a TGF-β1–inducible glycoprotein, in lung development. Deletion of Fstl1 in mice led to gene (13), encodes a secreted extracellular glycoprotein belong- postnatal lethality as a result of respiratory failure. Analysis of the ing to the Fst-SPARC family, whose amino acid sequence con- mutant phenotype showed that Fstl1 is essential for tracheal carti- tains a follistatin-like domain (14, 15). Its functions and the lage formation and alveolar maturation. Deletion of the Fstl1 gene underlying mechanism are poorly understood. Studies in zebra- resulted in malformed tracheal rings manifested as discontinued fish (16, 17) suggest a developmental role of Fstl1 in early dor- rings and reduced ring number. Fstl1-deficient mice displayed sep- soventral body axis establishment. In vitro studies have shown tal hypercellularity and end-expiratory atelectasis, which were as- that Fstl1 is one of the mesenchymal factors determining ovi- sociated with impaired differentiation of distal alveolar epithelial ductal epithelial cell fate (18). In this study, we generated Fstl1- cells and insufficient production of mature surfactant proteins. deficient mice to examine the role of Fstl1 in lung development Mechanistically, Fstl1 interacted directly with BMP4, negatively and found that Fstl1 is essential for normal tracheal formation as regulated BMP4/Smad1/5/8 signaling, and inhibited BMP4-induced well as alveolar maturation. Furthermore, we demonstrated that surfactant gene expression. Reducing BMP signaling activity by Fstl1 regulates the differentiation of lung epithelial cells, in part, Noggin rescued pulmonary atelectasis of Fstl1-deficient mice. through negative regulation of BMP4 signaling. Therefore, we provide in vivo and in vitro evidence to demonstrate that Fstl1 modulates lung development and alveolar maturation, in Results part, through BMP4 signaling. Generation of Fstl1-Deficient Mice. To determine the biological − function of Fstl1 in vivo, we first generated Fstl1+/ mice by fl − − lung atelectasis | trachea formation | surfactant protein C | intercrossing EIIa-Cre;Fstl1 ox/+ mice (Fig. S1 A and B). Fstl1 / − lung epithelial differentiation mice were then generated by intercrossing Fstl1+/ mice. Western blotting confirmed the loss of Fstl1 protein expression (Fig. 1A). −/− ung development is a well orchestrated process that is tightly Fstl1 pups were born alive at the expected Mendelian ratio Lregulated by transcription factors, hormones, growth factors, (27%, 127 of 472). However, all homozygous pups breathed ir- and other factors in temporal and spatial manners (1, 2). The regularly and displayed a cyanotic skin color, then died shortly −/− mouse lung is derived from foregut endoderm in an embryonic day after birth (Fig. 1B). In addition, Fstl1 neonates displayed (E) 9.5 embryo. Trachea arises from the more proximal foregut multiple defects, including abnormal dorsal–ventral pattern of tube, whereas the rest of the lung develops from two ventral buds the neural tube, hydroureter, and overall skeletal defects. Con- that form at the distal end of the trachea, and undergoes branching sistent with the pleiotropic developmental defects caused by the morphogenesis to produce the pulmonary tree (3, 4). This branching loss of Fstl1, in situ hybridization revealed widespread Fstl1 ex- morphogenesis is accompanied by differentiation of epithelial cell pression during mouse embryonic development, including in types along a proximal–distal axis, including bronchial Clara cells the lung (19). (proximal) and alveolar type I and type II epithelial cells (AEC-I and Fstl1 fi −/− AEC-II, respectively; distal) (5). These highly specialized cell types Tracheal Malformation in -De cient Mice. Fstl1 neonates had render specific functions in the respiratory tract, such as the func- soft and unusually large tracheal tubes (Fig. 1C). Transverse tional alveolar surface area formed by AEC-I and AEC-II cells for gas exchange (6). TGF-β superfamily growth factors regulate organogenesis, Author contributions: Y.G., Y.-G.C., D.J., and W.N. designed research; Y.G., Y.D., M.Y., L.Z., X.Y., J.S., L.Q., H.G., M.N., and T.F. performed research; S.I., X.G., Y.-G.C., and D.J. con- including that of the lung (1, 7). For example, they exert an in- tributed new reagents/analytic tools; Y.G., Y.D., S.I., Y.-G.C., D.J., and W.N. analyzed data; hibitory effect on lung branching morphogenesis (8). Interference and Y.G. and W.N. wrote the paper. of TGF-β signaling with a dominant-negative TβRII (9) or anti- The authors declare no conflict of interest. Smad2/3 oligos (10) in embryonic lung organ cultures stimulates This article is a PNAS Direct Submission. branching morphogenesis. BMP4 is dynamically expressed in the 1Y.G., Y.D., and M.Y. contributed equally to this work. distal epithelium; disruption of BMP4 signaling in lungs of Sp-C- 2To whom correspondence may be addressed. E-mail: [email protected], Xnoggin or Sp-C-dnAlk6 transgenic mice abrogates the proximal– [email protected], or [email protected]. distal patterning in the lung where distal epithelial differentiation This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. is inhibited while proximal differentiation is promoted (11, 12). 1073/pnas.1007293108/-/DCSupplemental. 7058–7063 | PNAS | April 26, 2011 | vol. 108 | no. 17 www.pnas.org/cgi/doi/10.1073/pnas.1007293108 Downloaded by guest on September 26, 2021 It has been suggested that tracheal cartilage formation is a multistep process. The committed mesenchymal cells first con- dense and proliferate to form cartilage primordia that prefigure the overall shape of future cartilages (E10.5–E12.5). Expression of cartilage-specific proteins (such as type II collagen) is then − − initiated and cells differentiate into chondrocytes (E13.5–E15.5). Fig. 1. Generation of Fstl1 / mice. (A) Western blot analysis of Fstl1 pro- teins from E15.5 embryos (Upper) or E18.5 lung tissues (Lower). (B) Exami- After E15.5, well formed C-rings can be observed (20). To further nation of neonates after birth revealed that Fstl1−/− neonates were cyanotic. examine the function of Fstl1 in cartilaginous development, we (C) Autopsy observation showed that WT lungs were expanded by in- generated stable clones overexpressing Fstl1 using murine mes- halation of air, which can be seen as air bubbles in the distal regions, but enchymal cells, ATDC5, which can differentiate into chon- − − Fstl1 / lungs were collapsed and did not show evidence of air in the distal drocytes in the presence of insulin-transferrin-sodium selenite airways (tr, trachea). (ITS) (21). As determined by MTT assay, Fstl1 increased the proliferation of mesenchymal cells (Fig. 2D). Fstl1 also strongly promoted ITS-induced Col2a1 mRNA expression (6.7 fold) by sections of E18.5 homozygous trachea revealed a striking de- −/− using quantitative RT-PCR (qRT-PCR). Collectively, Fstl1 is formed lumen. Fstl1 tracheas were enlarged at the upper and essential for all chondrogenic steps in the development of the lower levels but narrowed at the middle level, and their inner upper respiratory tract. Deletion of Fstl1 limits the proliferation margins were irregular, with many small folds sometimes ac- and differentiation of cartilaginous precursors, resulting in mal- − − companied by protuberances in the tracheal aperture (Fig. 2A formed rings during tracheal development. However, Fstl1 / and Fig. S2A). At birth [postnatal day (P) 0], apart from a few trachea with impaired cartilage rings does not develop significant − − instances of tracheal stenosis, most lumens of Fstl1 / tracheas stenosis, indicating that tracheal defects may not be the main − − (>80%) were larger than their WT controls (Fig. 2A and Fig. cause of respiratory failure in Fstl1 / neonates. S2A). These larger tracheas could be observed as early as E15.5 Lung Atelectasis in Fstl1-Deficient Mice. Gross phenotype of lung (Fig. S2B). Another consistent observation was a profound dis- − − − − / organization of the Fstl1 / tracheal epithelium (Fig. S2C). was largely normal in neonatal Fstl1 pups. Their lungs had − − E15.5 and E18.5 Fstl1 / trachea also displayed interrupted similar size and the correct number of lobes (Fig. 1C), and showed similar lung/body dry weight ratio compared with their WT lit- or truncated cartilages, whereas their WT littermates showed C- − − termates (Fstl1 / , 0.47%, n =7;Fstl1+/+, 0.48%, n = 10; P > shaped cartilage rings (Fig. 2A and Fig. S2 A and B). The larynx and − − 0.05). The striking abnormality of Fstl1 / lungs was their con- the trachea were greatly disorganized in all homozygous fetuses densed appearance with a few big air bubbles in the distal airways (Fig.
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