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Wa5 is a novel ENU-induced antimorphic allele of the epidermal growth factor receptor

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Abstract

Mice heterozygous for the N-ethyl-N-nitrosourea-induced Waved-5 (Wa5) mutation, isolated in a screen for dominant, visible mutations, exhibit a wavy coat similar to mice homozygous for the recessive Tgfawa1 or Egfrwa2 alleles. In this study, we show that Wa5 is a new allele of Egfr (EgfrWa5) containing a missense mutation within the coding region for the highly conserved DFG motif of the tyrosine kinase domain. In vivo analysis of placental development, modification of ApcMin tumorigenesis, and levels of EGF-dependent EGFR phosphorylation demonstrates that EgfrWa5 functions as an antimorphic allele, recapitulating many abnormalities associated with reduced EGFR activity. Furthermore, Egfrwa5 enhances EgfrWa2 compound or Tgfatm1Dcl double mutants exposing additional EGFR-dependent phenotypes. In vitro characterization shows that the antimorphic property of EgfrWa5 is caused by a kinase-dead receptor acting as a dominant negative.

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Acknowledgments

We wish to thank members of our labs for suggestions and critical review of the manuscript. We especially thank Reade Roberts for stimulating discussion and taking the mouse photos in Figure 3 and Lisa Mckie for arranging mouse shipments. We thank David Lee (UNC) for providing the Tgfatm1Dcl line. This work was supported by grants from NCI (CA092479 and CA084239) and NICHD (HD039896) to D.W.T. and the Medical Research Council UK to I.J.J.

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  1. Department of Genetics, University of North Carolina School of Medicine, CB#7264, Chapel Hill, North Carolina, 27599, USA

    Daekee Lee, Karen E. Strunk, Candice L. Bailey & David W. Threadgill

  2. MRC Human Genetics Unit, Western General Hospital, Edinburgh, EH4 2XU, United Kingdom

    Sally H. Cross, Joanne E. Morgan & Ian J. Jackson

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  1. Daekee Lee
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  2. Sally H. Cross
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  7. David W. Threadgill
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Correspondence to David W. Threadgill.

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Lee, D., Cross, S.H., Strunk, K.E. et al. Wa5 is a novel ENU-induced antimorphic allele of the epidermal growth factor receptor. Mamm Genome 15, 525–536 (2004). https://doi.org/10.1007/s00335-004-2384-2

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