Fetal and postnatal lung defects reveal a novel and required role for Fgf8 in lung development

Abstract

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.

Pbx1 activates Fgf10 in the mesenchyme of developing lungs

“…It also labels the neural crest and lungs, including the lung mesenchymal cells. The expression of Islet1 in those tissues has been documented by lineage tracing using Islet1Cre with a Rosa26 lacz reporter allele (Engleka et al, 2012;High et al, 2009;Yu et al, 2010). Furthermore, the unexpected normal heart morphogenesis of Islet1Cre Pbx1 f/f mice could be the result of the following factors.…”

Wnt and FGF mediated epithelial‐mesenchymal crosstalk during lung development

“…FGF8 and FGF18 are closely related ligands that are expressed in the developing lung epithelium, but the phenotype of Fgf18 ‐/‐ lungs is quite different from that of Fgf8 hypomorphs. Fgf18 ‐deficient mice have hypoplastic lungs with decreased cell proliferation and unaffected epithelial differentiation (Usui et al, ), whereas Fgf8 mutant lungs have a hyperplastic phenotype with distal epithelial and mesenchymal hyperproliferation, and disrupted epithelial differentiation (Yu et al, ). Moreover, Fgf18 overexpression during lung development results in ectopic cartilage formation (Whitsett et al, ).…”

The a“MAZE”ing World of Lung-Specific Transgenic Mice

“…The Islet1Cre line is a knock-in strain [78] and drives Cre expression throughout the pharyngeal endoderm, including the pulmonary epithelial precursors, and in a subset of mesenchymal cells [79]. Although it is not epithelial specific, it has been successfully used to study Fgf8 function during lung development [80]. …”