FGF-10 disrupts lung morphogenesis and causes pulmonary adenomas in vivo.
Transgenic mice in which fibroblast growth factor (FGF)-10 was expressed in the lungs of fetal and postnatal mice were generated with a doxycycline-inducible system controlled by surfactant protein (SP) C or Clara cell secretory protein (CCSP) promoter elements. Expression of FGF-10 mRNA in the fetal lung caused adenomatous malformations, perturbed branching morphogenesis, and caused respiratory failure at birth. When expressed after birth, FGF-10 caused multifocal pulmonary tumors. FGF-10-induced tumors were highly differentiated papillary and lepidic pulmonary adenomas. Epithelial cells lining the tumors stained intensely for thyroid transcription factor (TTF)-1 and SP-C but not CCSP, indicating that FGF-10 enhanced differentiation of cells to a peripheral alveolar type II cell phenotype. Withdrawal from doxycycline caused rapid regression of the tumors associated with rapid loss of the differentiation markers TTF-1, SP-B, and proSP-C. FGF-10 disrupted lung morphogenesis and induced multifocal pulmonary tumors in vivo and caused reversible type II cell differentiation of the respiratory epithelium.
Division of Pulmonary Biology, Children's Hospital Medical Center, 3333 Burnet Ave., Cincinnati, OH 45229-3039, USA.
J C
JC
Clark
J W
JW
Tichelaar
S E
SE
Wert
N
N
Itoh
A K
AK
Perl
M T
MT
Stahlman
J A
JA
Whitsett
D000236:Adenoma / Q000139:chemically induced* / Q000648:ultrastructure; D000818:Animals; D000831:Animals, Newborn / Q000254:growth & development*; D004318:Doxycycline; D005314:Embryonic and Fetal Development / Q000187:drug effects; D005333:Fetus / Q000502:physiology*; D051526:Fibroblast Growth Factor 10; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000494:pharmacology*; D036341:Intercellular Signaling Peptides and Proteins; D008168:Lung / Q000187:drug effects / Q000196:embryology* / Q000254:growth & development* / Q000378:metabolism; D008175:Lung Neoplasms / Q000139:chemically induced* / Q000648:ultrastructure; D051379:Mice; D008822:Mice, Transgenic / Q000235:genetics; D009687:Nuclear Proteins / Q000378:metabolism; D010455:Peptides / Q000378:metabolism; D011498:Protein Precursors / Q000378:metabolism; D011506:Proteins / Q000235:genetics / Q000494:pharmacology; D011510:Proteolipids / Q000378:metabolism; D037721:Pulmonary Surfactant-Associated Protein C; D011663:Pulmonary Surfactants / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D000074482:Thyroid Nuclear Factor 1; D014157:Transcription Factors / Q000378:metabolism; D014598:Uteroglobin
C496464:Fgf10 protein, mouse; D051526:Fibroblast Growth Factor 10; D036341:Intercellular Signaling Peptides and Proteins; C000614414:Nkx2-1 protein, mouse; D009687:Nuclear Proteins; D010455:Peptides; D011498:Protein Precursors; D011506:Proteins; D011510:Proteolipids; D037721:Pulmonary Surfactant-Associated Protein C; D011663:Pulmonary Surfactants; D012333:RNA, Messenger; C556390:Scgb1a1 protein, mouse; C489680:Sftpc protein, mouse; D000074482:Thyroid Nuclear Factor 1; D014157:Transcription Factors; C105511:surfactant protein B propeptide; D005346:Fibroblast Growth Factors; D014598:Uteroglobin; D004318:Doxycycline