Novel mechanisms in murine nitrofen-induced pulmonary hypoplasia: FGF-10 rescue in culture.
We evaluated the role of the key pulmonary morphogenetic gene fibroblast growth factor-10 (Fgf10) in murine nitrofen-induced primary lung hypoplasia, which is evident before the time of diaphragm closure. In situ hybridization and competitive RT-PCR revealed a profound disturbance in the temporospatial pattern as well as a 10-fold decrease in mRNA expression level of Fgf10 but not of the inducible inhibitor murine Sprouty2 (mSpry2) after nitrofen treatment. Exogenous FGF-10 increased branching not only of control lungs [13% (right) and 27% (left); P < 0.01] but also of nitrofen-exposed lungs [23% (right) and 77% (left); P < 0.01]. Expression of mSpry2 increased 10-fold with FGF-10 in both nitrofen-treated and control lungs, indicating intact downstream FGF signaling mechanisms after nitrofen treatment. We conclude that nitrofen inhibits Fgf10 expression, which is essential for lung growth and branching. Exogenous FGF-10 not only stimulates FGF signaling, marked by increased mSpry2 expression, in both nitrofen-treated and control lungs but also substantially rescues nitrofen-induced lung hypoplasia in culture.
Acosta
J M
JM
Division of Pediatric Surgery and Developmental Biology Program, Childrens Hospital Los Angeles Research Institute, Keck School of Medicine, University of Southern California, Los Angeles, California 90027, USA.
Thébaud
B
B
Castillo
C
C
Mailleux
A
A
Tefft
D
D
Wuenschell
C
C
Anderson
K D
KD
Bourbon
J
J
Thiery
J P
JP
Bellusci
S
S
Warburton
D
D
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D004622:Embryo, Mammalian / Q000378:metabolism / Q000502:physiology; D005314:Embryonic and Fetal Development / Q000187:drug effects; D051526:Fibroblast Growth Factor 10; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D047908:Intracellular Signaling Peptides and Proteins; D008168:Lung / Q000187:drug effects / Q000196:embryology* / Q000473:pathology*; D008565:Membrane Proteins; D051379:Mice; D010647:Phenyl Ethers / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases; D011506:Proteins / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D014018:Tissue Distribution
D048868:Adaptor Proteins, Signal Transducing; C496464:Fgf10 protein, mouse; D051526:Fibroblast Growth Factor 10; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D010647:Phenyl Ethers; D011506:Proteins; D012333:RNA, Messenger; D005346:Fibroblast Growth Factors; D017346:Protein Serine-Threonine Kinases; C118389:Spry2 protein, mouse; C007350:nitrofen