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Abnormal lung development and cleft palate in mice lacking TGF–β3 indicates defects of epithelial–mesenchymal interaction

Nature Genetics volume 11, pages 415–421 (1995)Cite this article

Abstract

A broad spectrum of biological activities has been proposed for transforming growth factor–β3(TGF–β 3). To study TGF–β3function in development, TGF–β3 null mutant mice were generated by gene–targeting. Within 20 hours of birth, homozygous TGF–β3−/− mice die with unique and consistent phenotypic features including delayed pulmonary development and defective palatogenesis. Unlike other null mutants with cleft palate, TGF–β3−/− mice lack other concomitant craniofacial abnormalities. This study demonstrates an essential function for TGF–β3 in the normal morphogenesis of palate and lung, and directly implicates this cytokine in mechanisms of epithelial–mesenchymal interaction.

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References

  1. Ten Dijke, P., Hansen, P., Iwata, K.K., Pieler, C. & Foulkes, J.G. Identification of another member of the transforming growth factor type β gene family. Proc. natn. Acad. Sci. U.S.A 85, 4715–4719 (1988).

    Article  CAS  Google Scholar 

  2. Derynck, R. et al A new type of transforming growth factor-b, TGF-β3 EMBO J. 7, 3737–3743 (1988).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Massagué, J. The transforming growth factor-β family. Ann. Rev. Cell Biol. 6, 597–641 (1990).

    Article  PubMed  Google Scholar 

  4. Roberts, A.B. & Sporn, M.B. The transforming growth factor βs, In Peptide growth factors and their receptor: Handbook of Experimental Pharmacology (eds. Sporn, M.B. & Roberts, A.B.) 412–472 (Springer-Verlag, Heidelberg, 1990).

    Chapter  Google Scholar 

  5. Graycar, J.L. et al. Human transforming growth factor (33: Recombinant expression, purification and biological activities in comparison with transforming growth factors-β1 and -β2. Molec. Endocrinol. 3, 1977–1986 (1989).

    Article  CAS  Google Scholar 

  6. Miller, D.A., Pelton, R.W., Derynck, R. & Moses, H.L. Transforming growth factor-β. A family of growth regulatory peptide. Ann. N. Y. Acad. Sci. 593, 208–217 (1990).

    Article  CAS  PubMed  Google Scholar 

  7. Roberts, A.B. & Sporn, M.B. Differential expression of the TGF-β isoforms in embryogenesis suggests specific roles in developing and adult tissues. Molec. Reprod. Dev. 32, 91–98 (1992).

    Article  CAS  PubMed  Google Scholar 

  8. Schmid, P., Cox, D., Bilbe, G., Maier, R. & McMaster, G.K. Differential expression of TGF-β1, β2 and β3 genes during mouse embryogenesis. Development 111, 117–130 (1991).

    CAS  PubMed  Google Scholar 

  9. Sharpe, P.M. & Ferguson, M.W.J. Mesenchymal influences on epithelial differentiation in developing systems. J. Cell Sci. Suppl. 10, 195–230 (1980).

    Google Scholar 

  10. Millan, F.A., Denhez, F., Kondaiah, P. & Akhurst, R.J. Embryonic gene expression patterns of TGF β1, β2 and β3 suggest different developmental functions in vivo. Development 111, 131–144 (1991).

    CAS  PubMed  Google Scholar 

  11. Vorbroker, O.K., Profitt, S.A., Nogee, L.M., Whitsett, J.A. Aberrant processing of surfactant protein C in hereditary SP-B deficiency. Am. J. Physiol. 268, L647–656 (1995).

    Article  CAS  PubMed  Google Scholar 

  12. Pourtois, M. Onset of the acquired potentiality for fusion in the palatal shelves of rats. J. Embryol. exp. Morph. 16, 171–182 (1966).

    CAS  PubMed  Google Scholar 

  13. Ferguson, M.W.J. Palate development. Development 103 Suppl., 41–60 (1988).

    PubMed  Google Scholar 

  14. Greene, R.M. Signal transduction during craniofacial development. Grit. Rev. Toxicol. 20, 137–153 (1989).

    Article  CAS  Google Scholar 

  15. Fitchett, J.E. & Hay, E.D. Medial edge epithelium transforms to mesenchyme after embryonic palatal shelves fuse. Dev. Biol. 131, 455–474 (1989).

    Article  CAS  PubMed  Google Scholar 

  16. Shuler, C.F., Guo, Y., Majumder, A. & Luo, R. Molecular and morphologic changes during the epithelial-mesenchymal transformation of palatal shelf medial edge epithelium in vitro. Int. J. dev. Biol. 35, 463–472 (1991).

    CAS  PubMed  Google Scholar 

  17. Shuler, C.F., Halpern, D.E., Quo, Y. & Sank, A.C. Medial edge epithelium fate traced by cell lineage analysis during epithelial-mesenchymal transformation in vivo. Dev. Biol. 154, 318–330 (1992).

    Article  CAS  PubMed  Google Scholar 

  18. Carette, M.J.M. & Ferguson, M.W.L. The fate of medial edge epithelial cells during palatal fusion in vitro: An analysis by Dil labeling and confocal microscopy. Development 114, 379–388 (1992).

    CAS  PubMed  Google Scholar 

  19. Fitzpatrick, D.R., Denhez, F., kondaiah, P. & Akhurst, R. Differential expression of TGF-beta isoforms in murine palatogenesis. Development 109, 585–595 (1990).

    CAS  PubMed  Google Scholar 

  20. Pelton, R.W., Hogan, B.L.M., Miller, D.A. & Moses, H.L. Differential expression of genes encoding TGFs β1, β2, and β3 during murine palate formation. Dev. Biol. 141, 456–460 (1990).

    Article  CAS  PubMed  Google Scholar 

  21. Brunet, C.L., Sharpe, P.M. & Ferguson, M.W.J. Inhibition of TGF-β3 (but not TGF-β1 or TGF-β2) activity prevents normal mouse embryonic palate fusion. Int. J. dev. Biol. 39, 345–355 (1995).

    CAS  PubMed  Google Scholar 

  22. Shapiro, B.L. & Sweney, L.R. Electron microscopic and histochemical examination of oral epithelial-mesenchymal interaction (programmed cell death). J. Dent. Res. 48, 652–660 (1969).

    Article  CAS  PubMed  Google Scholar 

  23. Hudson, C.D. & Shapiro, B.L. A autoradiographic study of DMA synthesis in embryonic palatal shelf epithelium with reference to the concept of programmed cell death. Arch. Oral. Biol. 18, 77–84 (1973).

    Article  CAS  PubMed  Google Scholar 

  24. Pratt, R.M. & Martin, G.R. Epithelial cell death and cAMP increase during palatal development. Proc. natn. Acad. Sci. U.S.A. 72, 874–877 (1975).

    Article  CAS  Google Scholar 

  25. Pratt, R.M. & Greene, R.M. Inhibition of palatal epithelial cell death by altered protein synthesis. Dev. Biol. 54, 135–145 (1976).

    Article  CAS  PubMed  Google Scholar 

  26. Potts, J.D., Dagle, J.M., Walder, J.A., Weeks, D.L. & Runyan, R.B. Epithelial-mesenchymal transformation of embryonic cardiac endothelial cells is inhibited by a modified antisense oligodeoxynucleotide to transforming growth factors β3. Proc. natn. Acad. Sci. U.S.A. 88, 1516–1520 (1991).

    Article  CAS  Google Scholar 

  27. Letterio, J.J. et al. Maternal rescue of transforming growth factor-β1 null mice. Science 264, 1936–1938 (1994).

    Article  CAS  PubMed  Google Scholar 

  28. Shannon, J.M. Induction of alveolar type II cell differentiation in foetal tracheal epithelium by grafted distal lung mesenchyme. Dev. Biol. 166, 600–614 (1994).

    Article  CAS  PubMed  Google Scholar 

  29. Minoo, P. & King, R.J. Epithelial-mesenchymal interactions in lung development. A Rev. Physiol. 56, 13–45 (1994).

    Article  CAS  Google Scholar 

  30. Jetten, A.M., Volberg, T.M., Nervi, C. & George, M.D. Positive and negative regulation of proliferation and differentiation in tracheobronchial epithelial cells. An. Rev. resp. Dis. 142, S36–39 (1990).

    Article  CAS  Google Scholar 

  31. Warburton, D. et al. Epigenetic role of epidermal growth factor expression and signalling in embryonic mouse lung morphogenesis. Dev. Biol. 149, 123–133 (1992).

    Article  CAS  PubMed  Google Scholar 

  32. Serra, R., Pelton, R.W. & Moses, H.L. TGF-β1 inhibits branching morphogenesis and N-myc expression in lung bud organ cultures. Development 120, 2153–2161 (1994).

    CAS  PubMed  Google Scholar 

  33. Khalil, N. et al. Increased production and immunohistochemical localization of transforming growth factor-beta in idiopathic pulmonary fibrosis. Am. J. resp. Cell molec. Biol. 5, 155–162 (1991).

    Article  CAS  Google Scholar 

  34. Denholm, E.M. & Rollins, S.M. Expression and secretion of transforming growth factor-beta by bleomycin-stimulated rat alveolar macrophages. Am. J. Physiol. 264, L36–42 (1993).

    CAS  PubMed  Google Scholar 

  35. Rijli, F.M. et al. A homeotic transformation is generated in the rostral branchial region of the head by disruption of Hoxa-2, which acts as a selector gene. Cell 75, 1333–1349 (1993).

    Article  CAS  PubMed  Google Scholar 

  36. Gendron-Maquire, M., Mallo, M., Zhang, M. & Gridley, T. Hoxa-2 mutant mice exhibit homeotic transformation of skeletal elements derived from cranial neural crest. Cell 75, 1317–1331 (1993).

    Article  Google Scholar 

  37. Satokata, I. & Maas, R. Msx1 deficient mice exhibit cleft palate and abnormalities of craniofacial and tooth development. Nature Genet. 6, 348–356 (1995).

    Article  Google Scholar 

  38. Matzuk, M.M. et al. Functional analysis of activins during mammalian development. Nature 374, 354–356 (1994).

    Article  Google Scholar 

  39. Matzuk, M.M. et al. Multiple defects and perinatal death in mice deficient in follistatin. Nature 374, 360–363 (1995).

    Article  CAS  PubMed  Google Scholar 

  40. Couture, L.A., Abbott, B.D. & Bimbaum, L.S. A critical review of the developmental toxicity and teratogenicity of 2,3,7,8-tetrachlorodi-benzo-p-dioxin: Recent advances towards understanding the mechanism. Teratology 42, 619–627 (1990).

    Article  CAS  PubMed  Google Scholar 

  41. Pratt, R.M., Dencker, L. & Diewert, V.M. 2,3,7,8 tetrachlorodibenzo-p-dioxin induced cleft palate in the mouse: evidence for alterations in palatal shelf fusion. Teratog. Carcinog. Mutagen. 4, 427–436 (1984).

    Article  CAS  PubMed  Google Scholar 

  42. Abbott, P.B., Perdew, G.H. & Birnbaum, L.S. Ah receptor in embryonic mouse palate and effects of TCDD on receptor expression. Tox. appl. Pharma. 126, 16–25 (1994).

    Article  CAS  Google Scholar 

  43. Muglia, L., Jacobson, L., Dikkies, P. & Majzoub, R.A. Corticotropin-releasing hormone deficiency reveals major fetal but not adult glucocorticoid need. Nature 373, 427–432 (1995).

    Article  CAS  PubMed  Google Scholar 

  44. Wang, J. et al. Cloning and expression of glucocorticoid-induced genes in fetal rat lung fibroblasts. J. biol. Chem. 270, 2722–2728 (1995).

    Article  CAS  PubMed  Google Scholar 

  45. Smith, B.T. & Post, M. Tissue interactions in The Lung vol. 1 (eds. Crystal, R.G. & West, J.B.) Vol 1, 671–676 (Raven Press, New York, 1991).

    Google Scholar 

  46. Collabrative Group of Antenatal Steroid Therapy. Effects of antenatal dexamethasone administration on the prevention of respiratory distress syndrome. Am. J. Obstet. Gynecol. 141, 276–287 (1981).

  47. Pelton, R.W., Saxena, B., Jones, M., Moses, H.L. & Gold, L.I. Immunohistochemical localization of TGF-β1, TGF-β2 and TGF-β3 in mouse embryo: expression patterns suggest multiple roles during embryonic development. J. Cell Biol. 115, 1091–1105 (1991).

    Article  CAS  PubMed  Google Scholar 

  48. Miller, D.A. et al. Complementary DMA cloning of the murine transforming growth factor β3 (TGFβ3) precursor and the comparative expression of TGFβ3 and TGFβ1 messenger RNA in murine embryos and adult tissues. Molec. Endocrinol. 3, 1926–1934 (1989).

    Article  CAS  Google Scholar 

  49. McLeod, J.M. Differential staining of cartilage and bone in whole mouse fetuses by Alcian blue and Alizarin red S. Teratology 22, 299–301 (1980).

    Article  CAS  PubMed  Google Scholar 

  50. Nagy, A., Rossant, J., Nagy, R., Abramow-Neweriy, W. & Roder, J.C. Derivatization of completely cell-culture-derived mice from early-passage embryonic stem cells. Proc. natn. Acad. Sci. U.S.A. 90, 8424–8428 (1993).

    Article  CAS  Google Scholar 

  51. Wurst, W & Joyner, A Production of targeted embryonic stem cell clones in Gene Targeting: A Practical Approach (ed. Joyner, A.L.) 31–62 (Oxford Univ. Press, U.K., 1993).

  52. Voncken, J.W et al. Increased neutrophil respiratory burst in BCR null mutants. Cell 80, 719–728 (1995).

    Article  CAS  PubMed  Google Scholar 

  53. Papaioannou, V.P & Johnson, R. Production of chimeras and genetically defined offspring from targeted ES cells In Gene Targeting: A Practical Approach. ed. Joyner, A.L.) 107–146 (Oxford Univ. Press, U.K., 1993).

    Google Scholar 

  54. Alonso, S, Minty, A, Bouriet, Y. & Buckingham, M. Comparison of three actin-coding sequences in the mouse; evolutionary relationships between the actin genes of warm-blooded vertebrates. J. molec. Evol. 23, 11–22 (1986).

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Pathology, Childrens Hospital of Los Angeles Research Institute, 4650 Sunset Boulevard, Los Angeles, California, 90027, USA

    Vesa Kaartinen, Jan Willem Voncken, Nora Heisterkamp & John Groffen

  2. Center for Craniofacial Molecular Biology, School of Dentistry, University of Southern California, Los Angeles, California, 90033, USA

    Charles Shuler, David Warburton & Ding Bu

  3. Departments of Surgery and Pediatrics, Childrens Hospital of Los Angeles Research Institute, 4650 Sunset Boulevard, Los Angeles, California, 90027, USA

    David Warburton

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  1. Vesa Kaartinen
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Kaartinen, V., Voncken, J., Shuler, C. et al. Abnormal lung development and cleft palate in mice lacking TGF–β3 indicates defects of epithelial–mesenchymal interaction. Nat Genet 11, 415–421 (1995). https://doi.org/10.1038/ng1295-415

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