Conditional expression of fibroblast growth factor-7 in the developing and mature lung.
Effects of fibroblast growth factor-7 (FGF-7) on lung morphogenesis, respiratory epithelial cell differentiation, and proliferation were assessed in transgenic mice in which the human FGF-7 cDNA was controlled by a conditional promoter under the direction of regulatory elements from either the human surfactant protein-C (SP-C) or rat Clara cell secretory protein (ccsp) genes. Expression of FGF-7 was induced in respiratory epithelial cells of the fetal lung by administration of doxycycline to the dam. Prenatally, doxycycline induced FGF-7 mRNA in respiratory epithelial cells in both Sp-c and Ccsp transgenic lines, increasing lung size and causing cystadenomatoid malformation. Postnatally, mice bearing both Ccsp-rtta and (Teto)(7)-cmv-fgf-7 transgenes survived, and lung morphology was normal. Induction of FGF-7 expression by doxycycline in the Ccsp-rtta x (Teto)(7)-cmv-fgf-7 mice caused marked epithelial cell proliferation, adenomatous hyperplasia, and pulmonary infiltration with mononuclear cells. Epithelial cell hyperplasia caused by FGF-7 was largely resolved after removal of doxycycline. Surfactant proteins, TTF-1, and aquaporin 5 expression were conditionally induced by doxycycline. The Sp-c-rtta and Ccsp-rtta activator mice provide models in which expression is conditionally controlled in respiratory epithelial cells in the developing and mature lung, altering lung morphogenesis, differentiation, and proliferation.
Tichelaar
J W
JW
Children's Hospital Medical Center, Division of Pulmonary Biology, Cincinnati, Ohio 45229-3039, USA.
Lu
W
W
Whitsett
J A
JA
D000818:Animals; D051402:Aquaporin 5; D020346:Aquaporins / Q000378:metabolism; D004318:Doxycycline / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism; D051526:Fibroblast Growth Factor 10; D051523:Fibroblast Growth Factor 7; D005346:Fibroblast Growth Factors; D018507:Gene Expression Regulation, Developmental; D006133:Growth Substances / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D017403:In Situ Hybridization; D008168:Lung / Q000254:growth & development*; D008565:Membrane Proteins; D051379:Mice; D008822:Mice, Transgenic; D009687:Nuclear Proteins / Q000378:metabolism; D010741:Phospholipases A / Q000037:antagonists & inhibitors; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D011510:Proteolipids / Q000235:genetics / Q000378:metabolism; D011663:Pulmonary Surfactants / Q000235:genetics / Q000378:metabolism; D051381:Rats; D000074482:Thyroid Nuclear Factor 1; D014157:Transcription Factors / Q000378:metabolism; D019076:Transgenes; D014598:Uteroglobin / Q000378:metabolism
C496036:AQP5 protein, human; C496038:Aqp5 protein, mouse; C496040:Aqp5 protein, rat; D051402:Aquaporin 5; D020346:Aquaporins; D004791:Enzyme Inhibitors; C496453:FGF7 protein, human; C496454:Fgf7 protein, mouse; C496455:Fgf7 protein, rat; D051526:Fibroblast Growth Factor 10; D006133:Growth Substances; D008565:Membrane Proteins; C000614412:NKX2-1 protein, human; C000614414:Nkx2-1 protein, mouse; C000614416:Nkx2-1 protein, rat; D009687:Nuclear Proteins; D011506:Proteins; D011510:Proteolipids; D011663:Pulmonary Surfactants; C556389:SCGB1A1 protein, human; C556390:Scgb1a1 protein, mouse; C556391:Scgb1a1 protein, rat; D000074482:Thyroid Nuclear Factor 1; D014157:Transcription Factors; D051523:Fibroblast Growth Factor 7; D005346:Fibroblast Growth Factors; D014598:Uteroglobin; D010741:Phospholipases A; D004318:Doxycycline