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Influence of Genetic Background on Knockout Mouse Phenotypes

  • Protocol
Gene Knockout Protocols

Part of the book series: Methods in Molecular Biology ((MIMB,volume 158))

Abstract

Once a knockout allele generated by gene targeting has been introduced into the germline of a mouse, the primary concern is to efficiently screen the animal for mutant phenotypes. This is not necessarily a trivial exercise given the high frequency of unexpected or lack of phenotypes. With the number of published knockout mouse strains approaching 1000, considerable experience has accumulated with respect to these concerns. Some of the most obvious approaches involve developmental surveys at the morphological and histological levels, physiological studies, perturbation of homeostatic balances, introduction of stress or injury, and analysis of mutant organs, tissues and cells in vitro. However, the history of mouse genetics, which in itself can be termed the study of strain-dependent phenotype variability, tells us that as a backdrop to these approaches the genetic background onto which the targeted allele is placed can cause considerable variation in phenotype. This variation can present itself as completely different phenotypes, as variations in penetrance of phenotype, or as variable expressivity of phenotype.

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References

  1. Shull, M. M., Ormsby, I., Kier, A. B., et al. (1992) Targeted disruption of the mouse transforming growth factor-beta 1 gene results in multifocal inflammatory disease. Nature 359, 693–699.

    Article  PubMed  CAS  Google Scholar 

  2. Kulkarni, A. B., Huh, C. G., Becker, D., et al. (1993) Transforming growth factor beta 1 null mutation in mice causes excessive inflammatory response and early death. Proc. Natl. Acad. Sci. USA 90, 770–774.

    Article  PubMed  CAS  Google Scholar 

  3. Dickson, M. C., Martin, J. S., Cousins, F. M., et al. (1995) Defective haematopoiesis and vasculogenesis in transforming growth factor-beta 1 knock out mice. Development 121, 1845–1854.

    PubMed  CAS  Google Scholar 

  4. Bonyadi, M., Rusholme, S. A., Cousins, F. M., et al. (1997) Mapping of a major genetic modifier of embryonic lethality in TGF beta 1 knockout mice. Nat. Genet. 15, 207–211.

    Article  PubMed  CAS  Google Scholar 

  5. Baribault, H., Price, J., Miyai, K., and Oshima, R. G. (1993) Mid-gestational lethality in mice lacking keratin 8. Genes Dev. 7, 1191–1202.

    Article  PubMed  CAS  Google Scholar 

  6. Baribault, H., Penner, J., Iozzo, R. V., and Wilson-Heiner, M. (1994) Colorectal hyperplasia and inflammation in keratin 8-deficient FVB/N mice. Genes Dev. 8, 2964–2973.

    Article  PubMed  CAS  Google Scholar 

  7. Pritchard, C. A., Bolin, L., Slattery, R., et al. (1996) Post-natal lethality and neurological and gastrointestinal defects in mice with targeted disruption of the A-Raf protein kinase gene. Curr. Biol. 6, 614–617.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  10. Boivin, G. P., O’Toole, B. A., Orsmby, I. E., et al. (1995) Onset and progression of pathological lesions in transforming growth factor-beta 1-deficient mice. American J. Pathol. 146, 276–288.

    CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  12. Ramirez-Solis, R., Zheng, H., Whiting, J., et al. (1993) Hoxb-4 (Hox-2.6) mutant mice show homeotic transformation of a cervical vertebra and defects in the closure of the sternal rudiments. Cell 73, 279–294.

    Article  PubMed  CAS  Google Scholar 

  13. Winnier, G., Blessing, M., Labosky, P. A., and Hogan, B. L. M. (1995) Bone morphogenetic protein-4 is required for mesoderm formation and patterning in the mouse. Genes Dev. 9, 2105–2116.

    Article  PubMed  CAS  Google Scholar 

  14. Sanford, L. P., Ormsby, I., de Gittenberger, G. A., et al. (1997) TGFbeta2 knock-out mice have multiple developmental defects that are non-overlapping with other TGFbeta knockout phenotypes. Development 124, 2659–2670.

    PubMed  CAS  Google Scholar 

  15. Proetzel, G., Pawlowski, S. A., Wiles, M. V., et al. (1995) Transforming growth factor-beta 3 is required for secondary palate fusion. Nat.Genet. 11, 409–414.

    Article  PubMed  CAS  Google Scholar 

  16. Kaartinen, V., Voncken, J. W., Shuler, C., et al. (1995) Abnormal lung development and cleft palate in mice lacking TGF-beta 3 indicates defects of epithelial-mesenchymal interaction. Nat.Genet. 11, 415–421.

    Article  PubMed  CAS  Google Scholar 

  17. Engle, S. J., Stockelman, M. G., Chen, J., et al. (1996) Adenine phospho-ribosyltransferase-deficient mice develop 2,8-dihydroxyadenine nephrolithiasis. Proc. Natl. Acad. Sci USA 93, 5307–5312.

    Article  PubMed  CAS  Google Scholar 

  18. Bierkamp, C., Mclaughlin, K. J., Schwarz, H., et al. (1996) Embryonic heart and skin defects in mice lacking plakoglobin. Dev. Biol. 180, 780–785.

    Article  PubMed  CAS  Google Scholar 

  19. Diebold, R. J., Eis, M. J., Yin, M., et al. (1995) Early-onset multifocal inflammation in the transforming growth factor beta 1-null mouse is lymphocyte mediated. Proc. Natl. Acad. Sci. USA 92, 12,215–12,219.

    Article  PubMed  CAS  Google Scholar 

  20. Letterio, J. J., Geiser, A. G., Kulkarni, A. B., et al. (1996) Autoimmunity associated with TGF-beta1-deficiency in mice is dependent on MHC class II antigen expression. J. Clin. Invest. 98, 2109–2119.

    Article  PubMed  CAS  Google Scholar 

  21. Groden, J., Thliveris, A., Samowitz, W., et al. (1991) Identification and characterization of the familial adenomatous polyposis coli gene. Cell 66, 589–600.

    Article  PubMed  CAS  Google Scholar 

  22. Su, L. K., Kinzler, K. W., Vogelstein, B., et al. (1992) Multiple intestinal neoplasia caused by a mutation in the murine homolog of the APC gene. Science 256, 668–670.

    Article  PubMed  CAS  Google Scholar 

  23. Moser, A. R., Dove, W. F., Roth, K. A., and Gordon, J. I. (1992) The Min (multiple intestinal neoplasia) mutation: its effect on gut epithelial cell differentiation and interaction with a modifier system. J. Cell Biol. 116, 1517–1526.

    Article  PubMed  CAS  Google Scholar 

  24. Dietrich, W. F., Lander, E. S., Smith, J. S., et al. (1993) Genetic identification of Mom-1, a major modifier locus affecting Min-induced intestinal neoplasia in the mouse. Cell 75, 631–639.

    Article  PubMed  CAS  Google Scholar 

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© 2001 Humana Press Inc., Totowa, NJ

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Sanford, L.P., Kallapur, S., Ormsby, I., Doetschman, T. (2001). Influence of Genetic Background on Knockout Mouse Phenotypes. In: Tymms, M.J., Kola, I. (eds) Gene Knockout Protocols. Methods in Molecular Biology, vol 158. Humana Press. https://doi.org/10.1385/1-59259-220-1:217

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  • DOI: https://doi.org/10.1385/1-59259-220-1:217

  • Publisher Name: Humana Press

  • Print ISBN: 978-0-89603-572-0

  • Online ISBN: 978-1-59259-220-3

  • eBook Packages: Springer Protocols

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