Skip to main content
PMC home page
Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1995 Dec 19;92(26):12461–12465. doi: 10.1073/pnas.92.26.12461

Pulmonary malformation in transgenic mice expressing human keratinocyte growth factor in the lung.

W S Simonet 1, M L DeRose 1, N Bucay 1, H Q Nguyen 1, S E Wert 1, L Zhou 1, T R Ulich 1, A Thomason 1, D M Danilenko 1, J A Whitsett 1
PMCID: PMC40377  PMID: 8618921

Abstract

Expression of human keratinocyte growth factor (KGF/FGF-7) was directed to epithelial cells of the developing embryonic lung of transgenic mice disrupting normal pulmonary morphogenesis during the pseudoglandular stage of development. By embryonic day 15.5(E15.5), lungs of transgenic surfactant protein C (SP-C)-KGF mice resembled those of humans with pulmonary cystadenoma. Lungs were cystic, filling the thoracic cavity, and were composed of numerous dilated saccules lined with glycogen-containing columnar epithelial cells. The normal distribution of SP-C proprotein in the distal regions of respiratory tubules was disrupted. Columnar epithelial cells lining the papillary structures stained variably and weakly for this distal respiratory cell marker. Mesenchymal components were preserved in the transgenic mouse lungs, yet the architectural relationship of the epithelium to the mesenchyme was altered. SP-C-KGF transgenic mice failed to survive gestation to term, dying before E17.5. Culturing mouse fetal lung explants in the presence of recombinant human KGF also disrupted branching morphogenesis and resulted in similar cystic malformation of the lung. Thus, it appears that precise temporal and spatial expression of KGF is likely to play a crucial role in the control of branching morphogenesis during fetal lung development.

Full text

PDF
12461

Images in this article

12462Fig. 1
on p.12462
12463Fig. 2
on p.12463
12463Fig. 3
on p.12463

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Aaronson S. A., Bottaro D. P., Miki T., Ron D., Finch P. W., Fleming T. P., Ahn J., Taylor W. G., Rubin J. S. Keratinocyte growth factor. A fibroblast growth factor family member with unusual target cell specificity. Ann N Y Acad Sci. 1991;638:62–77. doi: 10.1111/j.1749-6632.1991.tb49018.x. [DOI] [PubMed] [Google Scholar]
  2. Aaronson S. A., Falco J. P., Taylor W. G., Cech A. C., Marchese C., Finch P. W., Rubin J., Weissman B. E., Di Fiore P. P. Pathways in which growth factors and oncogenes interact in epithelial cell mitogenic signal transduction. Ann N Y Acad Sci. 1989;567:122–129. doi: 10.1111/j.1749-6632.1989.tb16464.x. [DOI] [PubMed] [Google Scholar]
  3. Aaronson S. A., Rubin J. S., Finch P. W., Wong J., Marchese C., Falco J., Taylor W. G., Kraus M. H. Growth factor-regulated pathways in epithelial cell proliferation. Am Rev Respir Dis. 1990 Dec;142(6 Pt 2):S7–10. doi: 10.1164/ajrccm/142.6_Pt_2.S7. [DOI] [PubMed] [Google Scholar]
  4. Bottaro D. P., Rubin J. S., Ron D., Finch P. W., Florio C., Aaronson S. A. Characterization of the receptor for keratinocyte growth factor. Evidence for multiple fibroblast growth factor receptors. J Biol Chem. 1990 Aug 5;265(22):12767–12770. [PubMed] [Google Scholar]
  5. Brinster R. L., Chen H. Y., Trumbauer M. E., Yagle M. K., Palmiter R. D. Factors affecting the efficiency of introducing foreign DNA into mice by microinjecting eggs. Proc Natl Acad Sci U S A. 1985 Jul;82(13):4438–4442. doi: 10.1073/pnas.82.13.4438. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Finch P. W., Rubin J. S., Miki T., Ron D., Aaronson S. A. Human KGF is FGF-related with properties of a paracrine effector of epithelial cell growth. Science. 1989 Aug 18;245(4919):752–755. doi: 10.1126/science.2475908. [DOI] [PubMed] [Google Scholar]
  7. Gerdes J., Schwab U., Lemke H., Stein H. Production of a mouse monoclonal antibody reactive with a human nuclear antigen associated with cell proliferation. Int J Cancer. 1983 Jan 15;31(1):13–20. doi: 10.1002/ijc.2910310104. [DOI] [PubMed] [Google Scholar]
  8. Glasser S. W., Korfhagen T. R., Wert S. E., Bruno M. D., McWilliams K. M., Vorbroker D. K., Whitsett J. A. Genetic element from human surfactant protein SP-C gene confers bronchiolar-alveolar cell specificity in transgenic mice. Am J Physiol. 1991 Oct;261(4 Pt 1):L349–L356. doi: 10.1152/ajplung.1991.261.4.L349. [DOI] [PubMed] [Google Scholar]
  9. Hilfer S. R. Development of terminal buds in the fetal mouse lung. Scan Electron Microsc. 1983;(Pt 3):1387–1401. [PubMed] [Google Scholar]
  10. Hilfer S. R., Rayner R. M., Brown J. W. Mesenchymal control of branching pattern in the fetal mouse lung. Tissue Cell. 1985;17(4):523–538. doi: 10.1016/0040-8166(85)90029-1. [DOI] [PubMed] [Google Scholar]
  11. Housley R. M., Morris C. F., Boyle W., Ring B., Biltz R., Tarpley J. E., Aukerman S. L., Devine P. L., Whitehead R. H., Pierce G. F. Keratinocyte growth factor induces proliferation of hepatocytes and epithelial cells throughout the rat gastrointestinal tract. J Clin Invest. 1994 Nov;94(5):1764–1777. doi: 10.1172/JCI117524. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Korfhagen T. R., Glasser S. W., Wert S. E., Bruno M. D., Daugherty C. C., McNeish J. D., Stock J. L., Potter S. S., Whitsett J. A. Cis-acting sequences from a human surfactant protein gene confer pulmonary-specific gene expression in transgenic mice. Proc Natl Acad Sci U S A. 1990 Aug;87(16):6122–6126. doi: 10.1073/pnas.87.16.6122. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Korfhagen T. R., Swantz R. J., Wert S. E., McCarty J. M., Kerlakian C. B., Glasser S. W., Whitsett J. A. Respiratory epithelial cell expression of human transforming growth factor-alpha induces lung fibrosis in transgenic mice. J Clin Invest. 1994 Apr;93(4):1691–1699. doi: 10.1172/JCI117152. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Mason I. J., Fuller-Pace F., Smith R., Dickson C. FGF-7 (keratinocyte growth factor) expression during mouse development suggests roles in myogenesis, forebrain regionalisation and epithelial-mesenchymal interactions. Mech Dev. 1994 Jan;45(1):15–30. doi: 10.1016/0925-4773(94)90050-7. [DOI] [PubMed] [Google Scholar]
  15. Orr-Urtreger A., Givol D., Yayon A., Yarden Y., Lonai P. Developmental expression of two murine fibroblast growth factor receptors, flg and bek. Development. 1991 Dec;113(4):1419–1434. doi: 10.1242/dev.113.4.1419. [DOI] [PubMed] [Google Scholar]
  16. Panos R. J., Rubin J. S., Csaky K. G., Aaronson S. A., Mason R. J. Keratinocyte growth factor and hepatocyte growth factor/scatter factor are heparin-binding growth factors for alveolar type II cells in fibroblast-conditioned medium. J Clin Invest. 1993 Aug;92(2):969–977. doi: 10.1172/JCI116673. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Peters K. G., Werner S., Chen G., Williams L. T. Two FGF receptor genes are differentially expressed in epithelial and mesenchymal tissues during limb formation and organogenesis in the mouse. Development. 1992 Jan;114(1):233–243. doi: 10.1242/dev.114.1.233. [DOI] [PubMed] [Google Scholar]
  18. Peters K., Werner S., Liao X., Wert S., Whitsett J., Williams L. Targeted expression of a dominant negative FGF receptor blocks branching morphogenesis and epithelial differentiation of the mouse lung. EMBO J. 1994 Jul 15;13(14):3296–3301. doi: 10.1002/j.1460-2075.1994.tb06631.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Pierce G. F., Yanagihara D., Klopchin K., Danilenko D. M., Hsu E., Kenney W. C., Morris C. F. Stimulation of all epithelial elements during skin regeneration by keratinocyte growth factor. J Exp Med. 1994 Mar 1;179(3):831–840. doi: 10.1084/jem.179.3.831. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Rubin J. S., Osada H., Finch P. W., Taylor W. G., Rudikoff S., Aaronson S. A. Purification and characterization of a newly identified growth factor specific for epithelial cells. Proc Natl Acad Sci U S A. 1989 Feb;86(3):802–806. doi: 10.1073/pnas.86.3.802. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Simonet W. S., Bucay N., Lauer S. J., Taylor J. M. A far-downstream hepatocyte-specific control region directs expression of the linked human apolipoprotein E and C-I genes in transgenic mice. J Biol Chem. 1993 Apr 15;268(11):8221–8229. [PubMed] [Google Scholar]
  22. Sugahara K., Rubin J. S., Mason R. J., Aronsen E. L., Shannon J. M. Keratinocyte growth factor increases mRNAs for SP-A and SP-B in adult rat alveolar type II cells in culture. Am J Physiol. 1995 Sep;269(3 Pt 1):L344–L350. doi: 10.1152/ajplung.1995.269.3.L344. [DOI] [PubMed] [Google Scholar]
  23. Ten Have-Opbroek A. A., Dubbeldam J. A., Otto-Verberne C. J. Ultrastructural features of type II alveolar epithelial cells in early embryonic mouse lung. Anat Rec. 1988 Aug;221(4):846–853. doi: 10.1002/ar.1092210409. [DOI] [PubMed] [Google Scholar]
  24. Ten Have-Opbroek A. A. Lung development in the mouse embryo. Exp Lung Res. 1991 Mar-Apr;17(2):111–130. doi: 10.3109/01902149109064406. [DOI] [PubMed] [Google Scholar]
  25. Ulich T. R., Yi E. S., Longmuir K., Yin S., Biltz R., Morris C. F., Housley R. M., Pierce G. F. Keratinocyte growth factor is a growth factor for type II pneumocytes in vivo. J Clin Invest. 1994 Mar;93(3):1298–1306. doi: 10.1172/JCI117086. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Vorbroker D. K., Profitt S. A., Nogee L. M., Whitsett J. A. Aberrant processing of surfactant protein C in hereditary SP-B deficiency. Am J Physiol. 1995 Apr;268(4 Pt 1):L647–L656. doi: 10.1152/ajplung.1995.268.4.L647. [DOI] [PubMed] [Google Scholar]
  27. Wert S. E., Glasser S. W., Korfhagen T. R., Whitsett J. A. Transcriptional elements from the human SP-C gene direct expression in the primordial respiratory epithelium of transgenic mice. Dev Biol. 1993 Apr;156(2):426–443. doi: 10.1006/dbio.1993.1090. [DOI] [PubMed] [Google Scholar]
  28. Wikenheiser K. A., Clark J. C., Linnoila R. I., Stahlman M. T., Whitsett J. A. Simian virus 40 large T antigen directed by transcriptional elements of the human surfactant protein C gene produces pulmonary adenocarcinomas in transgenic mice. Cancer Res. 1992 Oct 1;52(19):5342–5352. [PubMed] [Google Scholar]
  29. Wispé J. R., Warner B. B., Clark J. C., Dey C. R., Neuman J., Glasser S. W., Crapo J. D., Chang L. Y., Whitsett J. A. Human Mn-superoxide dismutase in pulmonary epithelial cells of transgenic mice confers protection from oxygen injury. J Biol Chem. 1992 Nov 25;267(33):23937–23941. [PubMed] [Google Scholar]
  30. Yi E. S., Yin S., Harclerode D. L., Bedoya A., Bikhazi N. B., Housley R. M., Aukerman S. L., Morris C. F., Pierce G. F., Ulich T. R. Keratinocyte growth factor induces pancreatic ductal epithelial proliferation. Am J Pathol. 1994 Jul;145(1):80–85. [PMC free article] [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES