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J Biol Chem, Vol. 275, Issue 16, 11858-11864, April 21, 2000

Conditional Expression of Fibroblast Growth Factor-7 in the Developing and Mature Lung*

Jay W. Tichelaar, Wei Lu, and Jeffrey A. WhitsettDagger

From the Children's Hospital Medical Center, Division of Pulmonary Biology, Cincinnati, Ohio 45229-3039

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 × (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.

* This work was supported by National Institutes of Health Grants HL-56387 and HL-41496 and the Cystic Fibrosis Foundation.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Dagger To whom correspondence should be addressed: Children's Hospital Medical Center, Division of Pulmonary Biology, 3333 Burnet Ave., Cincinnati, OH 45229-3039. Tel.: 513-636-4830; Fax: 513-636-7868; E-mail: jeff.whitsett@chmcc.org.

Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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Identification and isolation of mouse type II cells on the basis of intrinsic expression of enhanced green fluorescent protein
Am J Physiol Lung Cell Mol Physiol, September 1, 2003; 285(3): L691 - L700.
[Abstract] [Full Text] [PDF]

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 J. Am. Soc. Nephrol.Home page
T. Shigehara, C. Zaragoza, C. Kitiyakara, H. Takahashi, H. Lu, M. Moeller, L. B. Holzman, and J. B. Kopp
Inducible Podocyte-Specific Gene Expression in Transgenic Mice
J. Am. Soc. Nephrol., August 1, 2003; 14(8): 1998 - 2003.
[Abstract] [Full Text] [PDF]

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 EndocrinologyHome page
L. Yang, A. Naltner, and C. Yan
Overexpression of Dominant Negative Retinoic Acid Receptor {alpha} Causes Alveolar Abnormality in Transgenic Neonatal Lungs
Endocrinology, July 1, 2003; 144(7): 3004 - 3011.
[Abstract] [Full Text] [PDF]

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 Proc. Natl. Acad. Sci. USAHome page
P. Ray, Y. Devaux, D. B. Stolz, M. Yarlagadda, S. C. Watkins, Y. Lu, L. Chen, X.-f. Yang, and A. Ray
Inducible expression of keratinocyte growth factor (KGF) in mice inhibits lung epithelial cell death induced by hyperoxia
PNAS, May 13, 2003; 100(10): 6098 - 6103.
[Abstract] [Full Text] [PDF]

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 Am. J. Physiol. Cell Physiol.Home page
T. A. Tucker, K. Varga, Z. Bebok, A. Zsembery, N. A. McCarty, J. F. Collawn, E. M. Schwiebert, and L. M. Schwiebert
Transient transfection of polarized epithelial monolayers with CFTR and reporter genes using efficacious lipids
Am J Physiol Cell Physiol, March 1, 2003; 284(3): C791 - C804.
[Abstract] [Full Text] [PDF]

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 J. Biol. Chem.Home page
I. Hokuto, A.-K. T. Perl, and J. A. Whitsett
Prenatal, but Not Postnatal, Inhibition of Fibroblast Growth Factor Receptor Signaling Causes Emphysema
J. Biol. Chem., January 3, 2003; 278(1): 415 - 421.
[Abstract] [Full Text] [PDF]

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 Eur Respir JHome page
H. Fehrenbach, A. Fehrenbach, T. Pan, M. Kasper, and R.J. Mason
Keratinocyte growth factor-induced proliferation of rat airway epithelium is restricted to Clara cells in vivo
Eur. Respir. J., November 1, 2002; 20(5): 1185 - 1197.
[Abstract] [Full Text] [PDF]

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 Am. J. Physiol. Lung Cell. Mol. Physiol.Home page
T. H. Sisson, K. E. Hanson, N. Subbotina, A. Patwardhan, N. Hattori, and R. H. Simon
Inducible lung-specific urokinase expression reduces fibrosis and mortality after lung injury in mice
Am J Physiol Lung Cell Mol Physiol, November 1, 2002; 283(5): L1023 - L1032.
[Abstract] [Full Text] [PDF]

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 J. Biol. Chem.Home page
L. Zhang, M. Ikegami, C. R. Dey, T. R. Korfhagen, and J. A. Whitsett
Reversibility of Pulmonary Abnormalities by Conditional Replacement of Surfactant Protein D (SP-D) in Vivo
J. Biol. Chem., October 4, 2002; 277(41): 38709 - 38713.
[Abstract] [Full Text] [PDF]

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 Am. J. Physiol. Lung Cell. Mol. Physiol.Home page
F. Demayo, P. Minoo, C. G. Plopper, L. Schuger, J. Shannon, and J. S. Torday
Mesenchymal-epithelial interactions in lung development and repair: are modeling and remodeling the same process?
Am J Physiol Lung Cell Mol Physiol, September 1, 2002; 283(3): L510 - L517.
[Abstract] [Full Text] [PDF]

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 Proc. Natl. Acad. Sci. USAHome page
A.-K. T. Perl, S. E. Wert, A. Nagy, C. G. Lobe, and J. A. Whitsett
Early restriction of peripheral and proximal cell lineages during formation of the lung
PNAS, August 6, 2002; 99(16): 10482 - 10487.
[Abstract] [Full Text] [PDF]

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 Am. J. Physiol. Lung Cell. Mol. Physiol.Home page
C. Liu, E. E. Morrisey, and J. A. Whitsett
GATA-6 is required for maturation of the lung in late gestation
Am J Physiol Lung Cell Mol Physiol, August 1, 2002; 283(2): L468 - L475.
[Abstract] [Full Text] [PDF]

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 J. Biol. Chem.Home page
J. A. Whitsett, J. C. Clark, L. Picard, J. W. Tichelaar, S. E. Wert, N. Itoh, A.-K. T. Perl, and M. T. Stahlman
Fibroblast Growth Factor 18 Influences Proximal Programming during Lung Morphogenesis
J. Biol. Chem., June 14, 2002; 277(25): 22743 - 22749.
[Abstract] [Full Text] [PDF]

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 Am. J. Physiol. Lung Cell. Mol. Physiol.Home page
L. B. Ware and M. A. Matthay
Keratinocyte and hepatocyte growth factors in the lung: roles in lung development, inflammation, and repair
Am J Physiol Lung Cell Mol Physiol, May 1, 2002; 282(5): L924 - L940.
[Abstract] [Full Text] [PDF]

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 Am. J. Pathol.Home page
B. Zheng, Z. Zhang, C. M. Black, B. de Crombrugghe, and C. P. Denton
Ligand-Dependent Genetic Recombination in Fibroblasts : A Potentially Powerful Technique for Investigating Gene Function in Fibrosis
Am. J. Pathol., May 1, 2002; 160(5): 1609 - 1617.
[Abstract] [Full Text] [PDF]

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 J. Virol.Home page
N. Sato, K. Matsuda, C. Sakuma, D. N. Foster, R. W. Oppenheim, and H. Yaginuma
Regulated Gene Expression in the Chicken Embryo by Using Replication-Competent Retroviral Vectors
J. Virol., February 15, 2002; 76(4): 1980 - 1985.
[Abstract] [Full Text] [PDF]

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 Am. J. Respir. Cell Mol. Bio.Home page
K. S. Harrod and R. J. Jaramillo
Pseudomonas aeruginosa and Tumor Necrosis Factor-alpha Attenuate Clara Cell Secretory Protein Promoter Function
Am. J. Respir. Cell Mol. Biol., February 1, 2002; 26(2): 216 - 223.
[Abstract] [Full Text] [PDF]

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 DevelopmentHome page
H. Yang, M. M. Lu, L. Zhang, J. A. Whitsett, and E. E. Morrisey
GATA6 regulates differentiation of distal lung epithelium
Development, January 5, 2002; 129(9): 2233 - 2246.
[Abstract] [Full Text] [PDF]

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 Genes Dev.Home page
G. H. Fisher, S. L. Wellen, D. Klimstra, J. M. Lenczowski, J. W. Tichelaar, M. J. Lizak, J. A. Whitsett, A. Koretsky, and H. E. Varmus
Induction and apoptotic regression of lung adenocarcinomas by regulation of a K-Ras transgene in the presence and absence of tumor suppressor genes
Genes & Dev., December 15, 2001; 15(24): 3249 - 3262.
[Abstract] [Full Text] [PDF]

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 ChestHome page
J. A. Whitsett, S. W. Glasser, J. W. Tichelaar, A.-K. T. Perl, J. C. Clark, and S. E. Wert
Transgenic Models for Study of Lung Morphogenesis and Repair : Parker B. Francis Lecture
Chest, July 1, 2001; 120(2007): 27S - 30S.
[Full Text] [PDF]

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 Genes Dev.Home page
C. A. Cronin, W. Gluba, and H. Scrable
The lac operator-repressor system is functional in the mouse
Genes & Dev., June 15, 2001; 15(12): 1506 - 1517.
[Abstract] [Full Text] [PDF]

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 Am. J. Physiol. Lung Cell. Mol. Physiol.Home page
R. H. Costa, V. V. Kalinichenko, and L. Lim
Transcription factors in mouse lung development and function
Am J Physiol Lung Cell Mol Physiol, May 1, 2001; 280(5): L823 - L838.
[Abstract] [Full Text] [PDF]

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 Proc. Natl. Acad. Sci. USAHome page
B. Zhao, S. S. Chua, M. M. Burcin, S. D. Reynolds, B. R. Stripp, R. A. Edwards, M. J. Finegold, S. Y. Tsai, and F. J. DeMayo
Phenotypic consequences of lung-specific inducible expression of FGF-3
PNAS, April 25, 2001; (2001) 101116598.
[Abstract] [Full Text]

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 Am. J. Physiol. Lung Cell. Mol. Physiol.Home page
J. C. Clark, J. W. Tichelaar, S. E. Wert, N. Itoh, A.-K. T. Perl, M. T. Stahlman, and J. A. Whitsett
FGF-10 disrupts lung morphogenesis and causes pulmonary adenomas in vivo
Am J Physiol Lung Cell Mol Physiol, April 1, 2001; 280(4): L705 - L715.
[Abstract] [Full Text] [PDF]

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 J. Biol. Chem.Home page
Z. Zhu, B. Ma, R. J. Homer, T. Zheng, and J. A. Elias
Use of the Tetracycline-controlled Transcriptional Silencer (tTS) to Eliminate Transgene Leak in Inducible Overexpression Transgenic Mice
J. Biol. Chem., June 29, 2001; 276(27): 25222 - 25229.
[Abstract] [Full Text] [PDF]

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 Proc. Natl. Acad. Sci. USAHome page
B. Zhao, S. S. Chua, M. M. Burcin, S. D. Reynolds, B. R. Stripp, R. A. Edwards, M. J. Finegold, S. Y. Tsai, and F. J. DeMayo
Phenotypic consequences of lung-specific inducible expression of FGF-3
PNAS, May 8, 2001; 98(10): 5898 - 5903.
[Abstract] [Full Text] [PDF]


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