Fetal and postnatal lung defects reveal a novel and required role for Fgf8 in lung development.
The fibroblast growth factor, FGF8, has been shown to be essential for vertebrate cardiovascular, craniofacial, brain and limb development. Here we report that Fgf8 function is required for normal progression through the late fetal stages of lung development that culminate in alveolar formation. Budding, lobation and branching morphogenesis are unaffected in early stage Fgf8 hypomorphic and conditional mutant lungs. Excess proliferation during fetal development disrupts distal airspace formation, mesenchymal and vascular remodeling, and Type I epithelial cell differentiation resulting in postnatal respiratory failure and death. Our findings reveal a previously unknown, critical role for Fgf8 function in fetal lung development and suggest that this factor may also contribute to postnatal alveologenesis. Given the high number of premature infants with alveolar dysgenesis and lung dysplasia, and the accumulating evidence that short-term benefits of available therapies may be outweighed by long-term detrimental effects on postnatal alveologenesis, the therapeutic implications of identifying a factor or pathway that can be targeted to stimulate normal alveolar development are profound.
Yu
Shibin
S
Department of Pediatrics, University of Utah, Salt Lake City, UT 84112, USA.
Poe
Bryan
B
Schwarz
Margaret
M
Elliot
Sarah A
SA
Albertine
Kurt H
KH
Fenton
Stephen
S
Garg
Vidu
V
Moon
Anne M
AM
D000818:Animals; D000831:Animals, Newborn; D002454:Cell Differentiation; D049109:Cell Proliferation; D004622:Embryo, Mammalian / Q000378:metabolism; D004848:Epithelium / Q000378:metabolism / Q000473:pathology; D005333:Fetus / Q000196:embryology* / Q000378:metabolism*; D051524:Fibroblast Growth Factor 8 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D019426:Integrases / Q000378:metabolism; D008168:Lung / Q000002:abnormalities / Q000098:blood supply / Q000196:embryology* / Q000254:growth & development*; D008648:Mesoderm / Q000378:metabolism / Q000473:pathology; D051379:Mice; D009154:Mutation / Q000235:genetics
C496457:Fgf8 protein, mouse; D051524:Fibroblast Growth Factor 8; C045073:Cre recombinase; D019426:Integrases