Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Transforming growth factor–β3 is required for secondary palate fusion

Abstract

Mice lacking TGF–β3 exhibit an incompletely penetrant failure of the palatal shelves to fuse leading to cleft palate. The defect appears to result from impaired adhesion of the apposing medial edge epithelia of the palatal shelves and subsequent elimination of the mid–line epithelial seam. No craniofacial abnormalities were observed. This result demonstrates that TGF–β3 affects palatal shelf fusion Dy an intrinsic, primary mechanism rather than by effects secondary to craniofacial defects.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

  1. Roberts, A.B. & Sporn, M.B. The transforming growth factor betas. Peptide Growth Factors and Their Receptors — Handbook of Experimental Pathology (eds Sporn, M.B. & Roberts, A.B.) 419–472 (Springer-Veriag, New York, 1990).

    Chapter  Google Scholar 

  2. Kingsley, D.M., TGF-beta superfamily: new members, new receptors, and new genetic tests of function in different organisms. Genes Dev. 8, 133–146 (1994).

    Article  CAS  PubMed  Google Scholar 

  3. Massague, J., Attisano, L. & Wrana, J. The complex interactions of TGF-β receptors. Trends Cell Biol. 4, 172–178 (1994).

    Article  CAS  PubMed  Google Scholar 

  4. Pelton, R.W., Saxena, B., Jones, M., Moses, H.L. & Gold, L.I. Immunohistochemical localization of TGF beta 1, TGF beta 2, and TGF beta 3 in the mouse embryo: expression patterns suggest multiple roles during embryonic development. J. CellBiol. 115, 1091–1105 (1991).

    Article  CAS  Google Scholar 

  5. Schmid, P., Cox, D., Bilbe, G., Maier, R. & McMaster, G.K. Differential expression of TGF beta 1, beta 2 and beta 3 genes during mouse embryogenesis. Development 111, 117–130 (1991).

    CAS  PubMed  Google Scholar 

  6. Milan, F.A., Denhez, F., Koncjaiah, P. & Akhurst, R.J. Embryonic gene expression patterns of TGF beta 1, beta 2 and beta 3 suggest different developmental functions in vivo. Development 111, 131–143 (1991).

    Google Scholar 

  7. Fitzpatrick, D.R., Denhez, F., Kondaiah, P. & Akhurst, R.J. Differential expression of TGF beta isoforms in murine palatogenesis. Development 109, 585–695 (1990).

    CAS  PubMed  Google Scholar 

  8. Pelton, R.W., Hogan, B.L., Miller, D.A. & Moses, H.L. Differential expression of genes encoding TGFs beta 1, beta 2, and beta 3 during murine palate formation. Devl. Biol. 141, 456–460 (1990).

    Article  CAS  Google Scholar 

  9. Brunei, 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).

    Google Scholar 

  10. Chai, Y. et al. Specific transforming growth factor-beta subtypes regulate embryonic mouse Meckel's cartilage and tooth development. Devl. Biol. 162, 85–103 (1994).

    Article  CAS  Google Scholar 

  11. Runyan, R.B., Potts, J.D. & Weeks, D.L. TGF-beta 3-mediated tissue interaction during embryonic heart development. Molec. Reprod. & Dev. 32, 152–159 (1992).

    Article  CAS  Google Scholar 

  12. Robinson, S.D., Silberstein, G.B., Roberts, A.B., Flanders, K.C. & Daniel, C.W. Regulated expression and growth inhibitory effects of transforming growth factor-beta isoforms in mouse mammary gland development. Development 113, 867–878 (1991).

    CAS  PubMed  Google Scholar 

  13. Shah, M., Foreman, D.M. & Ferguson, M.W.J. Neutralisation of TGFβ1 and TGFβ2 or exogenous addition of TGFβ3 to cutaneous rat wounds reduces scarring. J. Cell Sci. 108, 985–1002 (1995).

    CAS  PubMed  Google Scholar 

  14. Pelton, R.W., Dickinson, M.E., Moses, H.L. & Hogan, B.L. In situ hybridization analysis of TGF beta 3 RNA expression during mouse development: comparative studies with TGF beta 1 and beta 2. Development 110, 609–620 (1990).

    CAS  PubMed  Google Scholar 

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

    PubMed  Google Scholar 

  16. Dixon, M.J. & Ferguson, M.W.J. The effects of epidermal growth factor, transforming growth factors alpha and bete and platelet-derived growth factor on murine palatal shelves in organ culture. Arch. Oral Biol. 37, 395–410 (1992).

    Article  CAS  PubMed  Google Scholar 

  17. Gehris, A.L. & Greene, R.M. Regulation of murine embryonic epithelial cell differentiation by transforming growth factors beta. Differentiation 49, 167–173 (1992).

    Article  CAS  PubMed  Google Scholar 

  18. Shull, M.M. et al. Targeted disruption of the mouse transforming growth factOMbete 1 gene results in multifocal inflammatory disease. Nature 359, 693–699 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Kulkami, A.B. et al. Transforming growth factor beta 1 null mutation in mice causes excessive inflammatory response and early death. Proc. natn. Acad. Sci. U.S.A 90, 770–774 (1993).

    Article  Google Scholar 

  20. Boivin, G.P. et al. Onset and progression of pathological lesions in transforming growth factornbete 1-deficient mice. Am. J. Pathol. 146, 276–288 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Kulkarni, A.B. et al. Transforming growth factor-beta 1 null mice. An animal model for inflammatory disorders. Am. J. Pathol. 146, 264–275 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Thomas, K.R. & Capecchi, M.R. Site-directed mutagenesis by gene targeting in mouse embryo-derived stem cells. Cell 51, 503–512 (1987).

    Article  CAS  PubMed  Google Scholar 

  23. Ferguson, M.W.J. Craniofacial malformations: towards a molecular understanding. Nature Genet. 6, 329–330 (1994).

    Article  CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  25. Greene, R.M. & Pratt, R.M. Developmental aspects of secondary palate formation. J. Embryol. exp. Morph. 36, 225–245 (1976).

    CAS  PubMed  Google Scholar 

  26. Morris-Wiman, J. & Brinkley, L. An extracellular matrix infrastructure provides support for murine secondary palatal shelf remodelling. Anat. Rec. 234, 575–586 (1992).

    Article  CAS  PubMed  Google Scholar 

  27. Ferguson, M.W.J. Palate development: mechanisms and malformations. Ir. J. Medical Sci. 156, 309–315 (1987).

    Article  CAS  Google Scholar 

  28. D'Angelo, M., Chen, J.M., Ugen, K. & Greene, R.M. TGF beta 1 regulation of collagen metabolism by embryonic palate mesenchymal cells. J. exp. Zool. 270, 189–201 (1994).

    Article  CAS  PubMed  Google Scholar 

  29. 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. Devl. Biol. 154, 318–330 (1992).

    Article  CAS  Google Scholar 

  30. Griffith, C.M. & Hay, E.D. Epithelial-mesenchymal transformation during palatal fusion: carboxyfluorescein traces cells at light and electron microscopic levels. Development 116, 1087–1099 (1992).

    CAS  PubMed  Google Scholar 

  31. Matzuk, M.M. et al. Functional analysis of activins during mammalian development. Nature 374, 354–356 (1995).

    Article  CAS  PubMed  Google Scholar 

  32. Matzuk, M.M., Kumar, T.R. & Bradley, A. Different phenotypes for mice deficient in either activins or activin receptor type II. Nature 374, 356–360 (1995).

    Article  CAS  PubMed  Google Scholar 

  33. 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 

  34. Gendron-Maguire, 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  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. Satokata, I. & Maas, R. Msx1 deficient mice exhibit cleft palate and abnormalities of craniofacial and tooth development. Nature Genet. 6, 348–356 (1994).

    Article  CAS  PubMed  Google Scholar 

  37. Kurihara, Y. et al. Elevated blood pressure and craniofacial abnormalities in mice deficient in endothelin-1. Nature 368, 703–710 (1994).

    Article  CAS  PubMed  Google Scholar 

  38. Martin, J.F., Bradley, A. & Olson, E.N. The pairecWike homeo box gene MHox is required for early events of skeletogenesis in multiple lineages. Genes Dev 9, 1237–1249 (1995).

    Article  CAS  PubMed  Google Scholar 

  39. Lohnes, D. et al. Function of retinoic acid receptor gamma in the mouse. Cell 73, 643–658 (1993).

    Article  CAS  PubMed  Google Scholar 

  40. Brown, K.S. Genetics of clefting in the mouse: a critique. Prog. clin. biol. Res. 46, 77–69 (1980).

    CAS  PubMed  Google Scholar 

  41. Letterio, J.J. et al. Maternal rescue of transforming growth factor-Beta 1 null mice. Science 264, 1936–1938 (1994).

    Article  CAS  PubMed  Google Scholar 

  42. Anscher, M.S. et al. Changes in plasma TGF beta levels during pulmonary radiotherapy as a predictor of the risk of developing radiation pneumonitis. Int. J. Radiat. Oncol., Biol., Phys. 30, 671–676 (1994).

    Article  CAS  Google Scholar 

  43. Wahl, S.M. Transforming growth factor beta (TGF-beta) in inflammation: a cause and a cure. J. din. Immunol. 12, 61–74 (1992).

    Article  CAS  Google Scholar 

  44. Chenevix-Trench, G., Jones, K., Green, A.C., Duffy, D.L. & Martin, N.G. Cleft lip with or without cleft palate: associations with transforming growth factor alpha and retinoic acid receptor loci. Am. J. hum. Genet. 51, 1377–1385 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Ardinger, H.H. et al. Association of genetic variation of the transforming growth factor-alpha gene with cleft lip and palate. Am. J. hum. Genet. 45, 348–353 (1989).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Shiang, R. et al. Association of transforming growth-factor alpha gene polymorphisms with nonsyndromic cleft palate only (CPO). Am. J. hum. Genet. 53, 836–843 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Hooper, M., Hardy, K., Handyside, A., Hunter, S. & Monk, M. HPRT-deficient (Lesch-Nyhan) mouse embryos derived from germline colonization by cultured cells. Nature 326, 292–295 (1987).

    Article  CAS  PubMed  Google Scholar 

  48. Laird, P.W. et al. Simplified mammalian DMA isolation procedure. Nud. Acids Res. 19, 4293 (1991).

    Article  CAS  Google Scholar 

  49. Proetzel, G. Functional analysis of transforming growth factor-beta-3 using gene targeting. Doctoral thesis, University of Cincinnati College of Medicine. 1–156 (1994).

    Google Scholar 

  50. Chomczynski, P. & Sacchi, N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Analyt. Biochem. 162, 156–159 (1987).

    Article  CAS  PubMed  Google Scholar 

  51. Keller, G., Kennedy, M., Papayannopoulou, T. & Wiles, M.V. Hematopoietic commitment during embryonic stem cell differentiation in culture. Molec. cell. Biol. 13, 473–486 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Wilson, J.G. Methods for administering agents and detecting malformation in experimental animals. In Teratology: principles and techniques (eds Wilson, J.G. & Warkany, J.) 262–277 (University of Chicago Press, Chicago, 1965).

    Google Scholar 

  53. Carette, M.J., Lane, E.B. & Ferguson, M.W. Differentiation of mouse embryonic palatal epithelium in culture: selective cytokeratin expression distinguishes between oral, medial edge and nasal epithelial cells. Differentiation 47, 149–161 (1991).

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Proetzel, G., Pawlowski, S., Wiles, M. et al. Transforming growth factor–β3 is required for secondary palate fusion. Nat Genet 11, 409–414 (1995). https://doi.org/10.1038/ng1295-409

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng1295-409

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing