Levels of mesenchymal FGFR2 signaling modulate smooth muscle progenitor cell commitment in the lung.
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 epithelial 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.
De Langhe
Stijn P
SP
Developmental Biology Program, Department of Surgery, Saban Research Institute of Childrens Hospital Los Angeles, CA 90027, USA.
Carraro
Gianni
G
Warburton
David
D
Hajihosseini
Mohammad K
MK
Bellusci
Saverio
S
D000818:Animals; D000831:Animals, Newborn; D019898:Autocrine Communication / Q000502:physiology; D002454:Cell Differentiation / Q000502:physiology; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D051526:Fibroblast Growth Factor 10 / Q000172:deficiency / Q000235:genetics; D005353:Fibronectins / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D006579:Heterozygote; D008168:Lung / Q000166:cytology* / Q000196:embryology; D008648:Mesoderm / Q000378:metabolism*; D051379:Mice; D032389:Myocytes, Smooth Muscle / Q000166:cytology*; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology*; D051153:Wnt Proteins / Q000378:metabolism
C496464:Fgf10 protein, mouse; D051526:Fibroblast Growth Factor 10; D005353:Fibronectins; D012333:RNA, Messenger; D051153:Wnt Proteins; D051497:Receptor, Fibroblast Growth Factor, Type 2