Temporal effects of Sprouty on lung morphogenesis.
Paracrine signaling mediated by FGF-10 and the FGF-R2IIIb receptor is required for formation of the lung. To determine the temporal requirements for FGF signaling during pulmonary morphogenesis, Sprouty-4 (Spry-4), an intracellular FGF receptor antagonist, was expressed in epithelial cells of the fetal lung under control of a doxycycline-inducible system. Severe defects in lobulation and severe lung hypoplasia were observed when Spry-4 was expressed throughout fetal lung development (E6.5-E18.5) or from E6.5 until E13.5. Effects of Spry-4 on branching were substantially reversed by removal of doxycycline from the dam at E12.5, but not at E13.5. In contrast, when initiated late in development (E12.5 to birth), Spry-4 caused less severe pulmonary hypoplasia. Expression of Spry-4 from E16.5 to E18.5 reduced lung growth and resulted in perinatal death due to respiratory failure. Expression of Spry-4 during the saccular and alveolar stages, from E18.5 to postnatal day 21, caused mild emphysema. These findings demonstrate that the embryonic-pseudoglandular stage is a critical time period during which Spry-sensitive pathways are required for branching morphogenesis, lobulation, and formation of the peripheral lung parenchyma.
Perl
Anne-Karina T
AK
Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229-3039, USA.
Hokuto
Isamu
I
Impagnatiello
Maria-Antonietta
MA
Christofori
Gerhard
G
Whitsett
Jeffrey A
JA
D000818:Animals; D000831:Animals, Newborn; D002454:Cell Differentiation; D004318:Doxycycline / Q000494:pharmacology; D005260:Female; D051526:Fibroblast Growth Factor 10; D005346:Fibroblast Growth Factors / Q000378:metabolism; D020869:Gene Expression Profiling; D008168:Lung / Q000098:blood supply / Q000187:drug effects / Q000196:embryology*; D051379:Mice; D008822:Mice, Transgenic; D009024:Morphogenesis / Q000187:drug effects; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000494:pharmacology*; D009924:Organ Culture Techniques; D011247:Pregnancy; D017468:Receptors, Fibroblast Growth Factor / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics*; D015398:Signal Transduction; D013997:Time Factors
C496464:Fgf10 protein, mouse; D051526:Fibroblast Growth Factor 10; D009419:Nerve Tissue Proteins; D017468:Receptors, Fibroblast Growth Factor; D012097:Repressor Proteins; C499037:Spry4 protein, mouse; D005346:Fibroblast Growth Factors; D004318:Doxycycline