FGF-1 and FGF-7 induce distinct patterns of growth and differentiation in embryonic lung epithelium.
Fibroblast growth factors (FGFs) and receptors (FGFRs) are expressed in the developing lung and appear to be major regulators of lung growth and differentiation. By using mesenchyme-free lung epithelial cultures we show that FGF-1 (aFGF) and FGF-7 (KGF) produce different effects in the developing lung. FGF-1 stimulates epithelial proliferation that results in bud formation (branching), while FGF-7 promotes epithelial proliferation that leads to formation of cyst-like structures. In addition, FGF-7 stimulates epithelial differentiation, stimulating expression of SP-A and SP-B mRNA throughout the explant, and inducing formation of focal areas of highly differentiated cells. The FGF-1 effects on differentiation are limited to induction of surfactant protein SP-B mRNA at the tips of the explant. The FGF-induced patterns of growth appear to correlate with the distribution of epithelial FGFRs mRNAs; FGFR-2 IIIb (KGFR) is diffusely expressed in the day 11 lung epithelium, while FGFR-4 appears in distal but not in proximal sites. We propose that cyst-like structures may result from FGF-7 binding to the uniformly distributed FGFR-2-IIIb. Lung bud formation may be regulated by FGF-1 and/or other ligands binding to FGFR-2 and a distally located FGFR, such as FGFR-4, leading to an increasing binding and activation of FGFRs at the tips of the explant. Thus, in the embryonic lung epithelium, growth effects of FGFs appear to be dependent on location of FGFRs, while effects on differentiation are ligand-dependent.
Cardoso
W V
WV
The Pulmonary Center, Department of Medicine, Boston University School of Medicine, Massachusetts 02118, USA. wcardoso@bupula.bu.edu
Itoh
A
A
Nogawa
H
H
Mason
I
I
Brody
J S
JS
D000818:Animals; D000831:Animals, Newborn; D004848:Epithelium / Q000378:metabolism / Q000502:physiology; D016220:Fibroblast Growth Factor 1 / Q000494:pharmacology*; D051526:Fibroblast Growth Factor 10; D051523:Fibroblast Growth Factor 7; D005346:Fibroblast Growth Factors; D015870:Gene Expression / Q000187:drug effects; D006133:Growth Substances / Q000494:pharmacology*; D017403:In Situ Hybridization; D008168:Lung / Q000187:drug effects / Q000196:embryology* / Q000378:metabolism; D051379:Mice; D009024:Morphogenesis / Q000187:drug effects; D009924:Organ Culture Techniques; D016133:Polymerase Chain Reaction; D011510:Proteolipids / Q000378:metabolism; D037662:Pulmonary Surfactant-Associated Protein A; D037661:Pulmonary Surfactant-Associated Proteins; D011663:Pulmonary Surfactants / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D051497:Receptor, Fibroblast Growth Factor, Type 2; D051499:Receptor, Fibroblast Growth Factor, Type 4; D017468:Receptors, Fibroblast Growth Factor / Q000378:metabolism
C496454:Fgf7 protein, mouse; D051526:Fibroblast Growth Factor 10; D006133:Growth Substances; D011510:Proteolipids; D037662:Pulmonary Surfactant-Associated Protein A; D037661:Pulmonary Surfactant-Associated Proteins; D011663:Pulmonary Surfactants; D012333:RNA, Messenger; D017468:Receptors, Fibroblast Growth Factor; D016220:Fibroblast Growth Factor 1; D051523:Fibroblast Growth Factor 7; D005346:Fibroblast Growth Factors; C496354:Fgfr2 protein, mouse; C496372:Fgfr4 protein, mouse; D020794:Receptor Protein-Tyrosine Kinases; D051497:Receptor, Fibroblast Growth Factor, Type 2; D051499:Receptor, Fibroblast Growth Factor, Type 4