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Mice mutant for Egfr and Shp2 have defective cardiac semilunar valvulogenesis

Nature Genetics volume 24, pages 296–299 (2000)Cite this article

Abstract

Atrioventricular and semilunar valve abnormalities are common birth defects, but how cardiac valvulogenesis is directed remains largely unknown. During studies of genetic interaction between Egfr, encoding the epidermal growth factor receptor, and Ptpn11, encoding the protein-tyrosine-phosphatase Shp2, we discovered that Egfr is required for semilunar, but not atrioventricular, valve development. Although unnoticed in earlier studies1,2, mice homozygous for the hypomorphic Egfr allele waved-2 (Egfrwa2/wa2) exhibit semilunar valve enlargement resulting from over-abundant mesenchymal cells. Egfr−/− mice (CD1 background) have similar defects. The penetrance and severity of the defects in Egfrwa2/wa2 mice are enhanced by heterozygosity for a targeted mutation of exon 2 of Ptpn11 (ref. 3). Compound (Egfrwa2/wa2:Ptpn11+/−) mutant mice also show premature lethality. Electrocardiography, echocardiography and haemodynamic analyses showed that affected mice develop aortic stenosis and regurgitation. Our results identify the Egfr and Shp2 as components of a growth-factor signalling pathway required specifically for semilunar valvulogenesis, support the hypothesis that Shp2 is required for Egfr signalling in vivo, and provide an animal model for aortic valve disease.

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Figure 1: Mating scheme of Egfrwa2/wa2 and Ptpn11-mutant mice.
Figure 2: Histological sections of semilunar valves from Egfrwa2/wa2 and Ptpn11-mutant mice stained with haematoxylin and eosin (a–f) or Masson trichrome (g–i).
Figure 3: The largest diameter of the aortic valve in serial sections of newborn (a,c,d) or adult (6–9 months old) (b) mice was measured microscopically.
Figure 4: Echocardiographic analysis.

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References

  1. Mclaren, A. & Bowman, P. Mouse chimaeras derived from fusion of embryos differing by nine genetic factors. Nature 224, 238–240 (1969).

    Article  CAS  Google Scholar 

  2. Luettke, N.C. et al. The mouse waved-2 phenotype results from a point mutation in the EGF receptor tyrosine kinase. Genes Dev. 8, 399–413 (1994).

    Article  Google Scholar 

  3. Arrandale, J.M. et al. Insulin signaling in mice expressing reduced levels of Syp. J. Biol. Chem. 271, 21353–21358 (1996).

    Article  CAS  Google Scholar 

  4. Van Vactor, D., O'Reilly, A.O. & Neel, B.G. Genetic analysis of protein tyrosine phosphatases. Curr. Opin. Genet. Dev. 8, 112–126 (1998).

    Article  Google Scholar 

  5. McLaren, A. The microscopic appearance of waved-2 mouse hairs. Genet. Res. 17, 257–260 (1971).

    Article  CAS  Google Scholar 

  6. Sibilia, M. & Wagner, E.F. Strain-dependent epithelial defects in mice lacking the EGF receptor. Science 269, 234–237 (1995).

    Article  CAS  Google Scholar 

  7. 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 

  8. 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 

  9. Sibilia, M., Steinbach, J.P., Stingl, L., Aguzzi, A. & Wagner, E.F. A strain-independent postnatal neurodegeneration in mice lacking the EGF receptor. EMBO J. 13, 719–731 (1998).

    Article  Google Scholar 

  10. Saxton, T.M. et al. Abnormal mesoderm patterning in mouse embryos mutant for the SH2 tyrosine phosphatase SHP-2. EMBO J. 16, 2352–2364 (1997).

    Article  CAS  Google Scholar 

  11. Wang, D.Z.M. et al. Mutation in Sos1 dominantly enhances a weak allele of the EGFR, demonstrating a requirement for Sos1 in EGFR signaling and development. Genes Dev. 11, 309–320 (1997).

    Article  CAS  Google Scholar 

  12. Qu, C.K., Yu, W.M., Azzarelli, B. & Feng, G.-S Genetic evidence that SHP-2 tyrosine phosphatase is a signal enhancer of the epidermal growth factor receptor in mammals. Proc. Natl Acad. Sci. USA 96, 8528–8533 (1999).

    Article  CAS  Google Scholar 

  13. Greco, T.L. et al. Analysis of the vestigial tail mutation demonstrates that Wnt-3a gene dosage regulates mouse axial development. Genes Dev. 10, 313–324 (1996).

    Article  CAS  Google Scholar 

  14. Takada, S. et al. Wnt-3a regulates somites and tail-bud formation in the mouse embryo. Genes Dev. 8, 174–189 (1994).

    Article  CAS  Google Scholar 

  15. Kirby, M.L. & Waldo, K.L. Neural crest and cardiovascular patterning. Circ. Res. 77, 211–215 (1995).

    Article  CAS  Google Scholar 

  16. Luetteke, N.C. et al. Targeted inactivation of the EGF and amphiregulin genes reveals distinct roles for EGF receptor ligands in mouse mammary gland development. Development 126, 2739–2750 (1999).

    CAS  PubMed  Google Scholar 

  17. Potts, J. & Runyan, R. Epithelial-mesenchymal cell transformation in the embryonic heart can be mediated, in part, by transforming growth factor β. Dev. Biol. 134, 392–401 (1989).

    Article  CAS  Google Scholar 

  18. 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 factor β 3. Proc. Natl Acad. Sci. USA 88, 1516–1520 (1991).

    Article  CAS  Google Scholar 

  19. Clark, E.B., Markwald, R.R. & Takao, A. Overview: cardiac morphogenesis. in Developmental Mechanisms of Heart Disease 157–168 (Futura, Armonk, 1995).

    Google Scholar 

  20. Lakkis, M.M. & Epstein, J.A. Neurofibromin modulation of ras activity is required for normal endocardial-mesenchymal transformation in the developing heart. Development 125, 4359–4367 (1998).

    CAS  PubMed  Google Scholar 

  21. Kretzschmar, M., Doody, J. & Massague, J. Opposing BMP and EGF signalling pathways converge on the TGF-β family mediator Smad1. Nature 389, 618–622 (1997).

    Article  CAS  Google Scholar 

  22. Gill, G.N. & Lazar, C.S. Increased phosphotyrosine content and inhibition of proliferation in EGF-treated A431 cells. Nature 293, 305–307 (1981).

    Article  CAS  Google Scholar 

  23. Barnes, D.W. Epidermal growth factor inhibits growth of A431 human epidermoid carcinoma in serum-free cell culture. J. Cell Biol. 93, 1–4 (1982).

    Article  CAS  Google Scholar 

  24. MacLeod, C.L., Luk, A., Castagnola, J., Cronin, M. & Mendelsohn, J. EGF induces cell cycle arrest of A431 human epidermoid carcinoma cells. J. Cell Physiol. 127, 175–182 (1986).

    Article  CAS  Google Scholar 

  25. Erickson, S.L. et al. ErbB3 is required for normal cerebellar and cardiac development: a comparison with ErbB2- and heregulin-deficient mice. Development 124, 4999–5011 (1997).

    CAS  PubMed  Google Scholar 

  26. Carraway, K.L.I. & Cantley, L.C. A new acquaintance for ErB3 and ErB4: a role for receptor heterodimerization in growth signaling. Cell 78, 5–8 (1994).

    Article  CAS  Google Scholar 

  27. Ranger, A.M. et al. The transcription factor NF-ATc is essential for cardiac valve formation. Nature 392, 186–189 (1998).

    Article  CAS  Google Scholar 

  28. de la Pompa, J.L. et al. Role of the NF-ATc transcription factor in morphogenesis of cardiac valves and septum. Nature 392, 182–186 (1998).

    Article  Google Scholar 

  29. Kupershmidt, S. et al. Replacement by homologous recombination of the minK gene with lacZ reveals restriction of minK expression to the mouse cardiac conduction system. Circ. Res. 84, 146–152 (1999).

    Article  CAS  Google Scholar 

  30. Lorenz, J.N. & Robbins, J. Measurement of intraventricular pressure and cardiac performance in the intact closed-chest anesthetized mouse. Am. J. Physiol. 272, 1137–1146 (1997).

    Google Scholar 

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Acknowledgements

We thank J. DeAngelis for help with electrocardiography; K. Converso for assistance with echocardiography; and S. Izumo, W. Quist and M. Mercola for helpful comments and criticisms. This work was supported by NIH grants R01 CA49152 and P50 HL56993-01 to B.G.N. and by HD26722 to T.M. L.D.K. is supported by an NRSA from the NIH.

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Authors and Affiliations

  1. Hematology/Oncology Division, Cancer Biology Program, Boston, Massachusetts, USA

    Binbin Chen, Lori D. Klaman & Benjamin G. Neel

  2. Cardiology Division, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA

    Thomas G. Hampton, Ju-feng Wang, Pamela S. Douglas & James P. Morgan

  3. Department of Pathology, School of Veterinary Medicine, Tufts University, Boston, Massachusetts, USA

    Roderick T. Bronson

  4. Department of Genetics, Case Western Reserve University, Cleveland, Ohio, USA

    Patricia J. Green & Terry Magnuson

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Correspondence to Benjamin G. Neel.

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Chen, B., Bronson, R., Klaman, L. et al. Mice mutant for Egfr and Shp2 have defective cardiac semilunar valvulogenesis. Nat Genet 24, 296–299 (2000). https://doi.org/10.1038/73528

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