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Epidermal growth factor receptor function is necessary for normal craniofacial development and palate closure

Abstract

Craniofacial malformations are among the most frequent congenital birth defects in humans; cleft palate, that is inadequate fusion of the palatal shelves, occurs with an annual incidence of 1 in 700 to 1 in 1,000 live births among individuals of European descent1. The secondary palate arises as bilateral outgrowths from the maxillary processes2, and its formation depends on the coordinated development of craniofacial structures including the Meckel's cartilage and the mandible3. Cleft lip and palate syndromes in humans are associated with polymorphisms in the gene (TGFA) encoding transforming growth factor-α (TGF-α), an epidermal growth factor receptor (EGFR) ligand made by most epithelia1,4. Here we have characterized craniofacial development in Egfr -deficient (Egfr-/-) mice. Newborn Egfr-/- mice have facial mediolateral defects including narrow, elongated snouts, underdeveloped lower jaw and a high incidence of cleft palate. Palatal shelf explants from Egfr-/- mice fused, but frequently had residual epithelium in the midline. In addition, morphogenesis of Meckel's cartilage was deficient in cultured mandibular processes from Egfr-/- embryos. The secretion of matrix metalloproteinases (MMPs) was diminished in Egfr-/- explants, consistent with the ability of EGF to increase MMP secretion and with the decreased MMP expression caused by inhibition of Egfr signalling in wild-type explants. Accordingly, inactivation of MMPs in wild-type explants phenocopied the defective morphology of Meckel's cartilage seen in Egfr-/- explants. Our results indicate that EGFR signalling is necessary for normal craniofacial development and that its role is mediated in part by its downstream targets, the MMPs, and may explain the genetic correlation of human cleft palate with polymorphisms in TGFA.

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Figure 1: Wild-type and Egfr-/- newborn mice differ in craniofacial appearance.
Figure 2: Egfr inactivation results in cleft palate in vivo and in residual medial-edge epithelium in vitro.
Figure 3: Inactivation of Egfr function perturbs the development of Meckel's cartilage in vitro.
Figure 4: Egfr signalling stimulates gelatinase secretion in cultured E10.5 branchial arches.
Figure 5: Egfr function is mediated by MMPs.

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References

  1. 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 α and retinoic acid receptor loci. Am. J. Hum. Genet. 51, 1377–1385 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    PubMed  Google Scholar 

  3. Seegmiller, R.E. & Fraser, F.C. Mandibular growth retardation as a cause of cleft palate in mice homozygous for the chondrodysplasia gene. J. Embryol. Exp. Morphol. 38, 227– 238 (1977).

    CAS  PubMed  Google Scholar 

  4. Shiang, R. et al. Association of transforming growth-factor α gene polymorphism with nonsyndromic cleft palate only (CPO). Am. J. Hum. Genet. 53, 836–843 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Iamaroon, A., Tait, B. & Diewert, V.M. Cell proliferation and expression of EGF, TGF-α, and EGF receptor in the developing primary palate. J. Dent. Res. 75, 1534–1539 ( 1996).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  7. Shum, L. et al. EGF abrogation-induced fusilli-form dysmorphogenesis of Meckel's cartilage during embryonic mouse mandibular morphogenesis in vitro. Development 118, 903–917 (1993).

    CAS  PubMed  Google Scholar 

  8. Partanen, A.M. & Thesleff, I. Localization and quantitation of 125I-epidermal growth factor binding in mouse embryonic tooth and other embryonic tissues at different developmental stages. Dev. Biol. 120, 186–197 ( 1987).

    Article  CAS  Google Scholar 

  9. Miettinen, P.J. et al. Epithelial immaturity and multiorgan failure in mice lacking epidermal growth factor receptor. Nature 376, 337–341 (1995).

    Article  CAS  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  11. Shuler, C.F. Programmed cell death and cell transformation in craniofacial development. Crit. Rev. Oral Biol. Med. 6, 202– 217 (1995).

    Article  CAS  Google Scholar 

  12. Chin, J.R. & Werb, Z. Matrix metalloproteinases regulate morphogenesis, migration and remodeling of epithelium, tongue, skeletal muscle and cartilage in the mandibular arch. Development 124 , 1519–1530 (1997).

    CAS  PubMed  Google Scholar 

  13. van der Zee, E., Jansen, I., Hoeben, K., Beertsen, W. & Everts, V. EGF and IL-1 α modulate the release of collagenase, gelatinase and TIMP-1 as well as the release of calcium by rabbit calvarial bone explants. J. Periodontal Res. 33, 65 –72 (1998).

    CAS  PubMed  Google Scholar 

  14. Sibilia, M. & Wagner, E. Strain-dependent epithelial defects in mice lacking EGF receptor. Science 269, 234–238 (1995).

    Article  CAS  Google Scholar 

  15. Threadgill, D.W. et al. Targeted disruption of mouse EGF receptor: effect of genetic background on mutant phenotype. Science 269, 230–234 (1995).

    Article  CAS  Google Scholar 

  16. Wilson, J.B. et al. Transgenic mouse model of X-linked cleft palate. Cell Growth Differ. 4, 67–76 (1993).

    CAS  PubMed  Google Scholar 

  17. Diehl, S.R. & Erickson, R.P. Genome scan for teratogen-induced clefting susceptibility loci in the mouse: evidence of both allelic and locus heterogeneity distinguishing cleft lip and palate. Proc. Natl Acad. Sci. USA 94, 5231–5236 ( 1997).

    Article  CAS  Google Scholar 

  18. Neel, J.V. A study of major congenital defects in Japanese infants. Am. J. Hum. Genet. 10, 398–445 (1958).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Chung, C.S. & Myrianthopoulos, N.C. Racial and prenatal factors in major congenital malformations. Am. J. Hum. Genet. 20, 44–60 (1968).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Christensen, K., Schmidt, M.M., Væth, M. & Olsen, J. Absence of an environmental effect on the recurrence of facial-cleft defects. N. Engl. J. Med. 333, 161– 164 (1995).

    Article  CAS  Google Scholar 

  21. Abbott, B.D. Review of the interaction between TCDD and glucocorticoids in embryonic palate. Toxicology 105, 365–373 (1995).

    Article  CAS  Google Scholar 

  22. Abbott, B.D. & Pratt, R.M. Retinoids and EGF alter embryonic mouse palatal epithelial and mesenchymal cell differentiation in organ culture. J. Craniofac. Genet. Dev. Biol. 7, 219– 240 (1987).

    CAS  PubMed  Google Scholar 

  23. Satokata, I. & Maas, R. Msx1-deficient mice exhibit cleft palate and abnormalities of craniofacial and tooth development. Nature Genet. 6, 348–355 (1994).

    Article  CAS  Google Scholar 

  24. Kaartinen, V. et al. Abnormal lung development and cleft palate in mice lacking TGF-β3 indicates defects of epthelial-mesenchymal interaction. Nature Genet. 11, 415–421 (1995).

    Article  CAS  Google Scholar 

  25. Lidral, A.C. et al. Association of Msx1 and Tgfβ3 with nonsyndromic clefting in humans. Am. J. Hum. Genet. 63, 557–568 (1998).

    Article  CAS  Google Scholar 

  26. Mitchell, L.E. Transforming growth factor α locus and non-syndromic cleft lip with or without cleft palate: a reappraisal. Genet. Epidemiol. 14, 231–240 (1997).

    Article  CAS  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Sheehan, D.C. & Hrapchak, B.B. Theory and Practice of Histotechnology (C.V. Mosby, St. Louis, 1980).

    Google Scholar 

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Acknowledgements

We thank J. Berger for technical assistance and J. Helms for a critical reading of the manuscript. This work was supported by grants from the National Institutes of Health (DE10306 to Z.W. and CA54826 to R.D.; AR41114 to L.S. and H.S.) and the Academy of Finland (P.J.M.).

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Correspondence to Päivi J. Miettinen.

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Miettinen, P., Chin, J., Shum, L. et al. Epidermal growth factor receptor function is necessary for normal craniofacial development and palate closure. Nat Genet 22, 69–73 (1999). https://doi.org/10.1038/8773

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