Skip to main content
PMC home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1996 Mar 15;97(6):1360–1365. doi: 10.1172/JCI118555

Targeted mutagenesis: analysis of phenotype without germ line transmission.

A Nagy 1, J Rossant 1
PMCID: PMC507193  PMID: 8617866

Abstract

The available techniques for directed gene manipulation in the mouse are unprecedented in any multicellular organism and make the mouse an invaluable tool for unraveling all aspects of mammalian biology. To realize fully the potential of these genetic tools requires that phenotypic analysis be efficient, rapid, and complete. Genetic chimeras and mosaics, in which mutant cells are mixed with wild-type cells, can be used to augment standard analysis of intact mutant animals and alleviate the time required and the expense involved in generating and maintaining multiple strains of mutant mice.

Full Text

The Full Text of this article is available as a PDF (125.9 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Ang S. L., Rossant J. HNF-3 beta is essential for node and notochord formation in mouse development. Cell. 1994 Aug 26;78(4):561–574. doi: 10.1016/0092-8674(94)90522-3. [DOI] [PubMed] [Google Scholar]
  2. Beddington R. S., Robertson E. J. An assessment of the developmental potential of embryonic stem cells in the midgestation mouse embryo. Development. 1989 Apr;105(4):733–737. doi: 10.1242/dev.105.4.733. [DOI] [PubMed] [Google Scholar]
  3. Capecchi M. R. Altering the genome by homologous recombination. Science. 1989 Jun 16;244(4910):1288–1292. doi: 10.1126/science.2660260. [DOI] [PubMed] [Google Scholar]
  4. Chen J., Lansford R., Stewart V., Young F., Alt F. W. RAG-2-deficient blastocyst complementation: an assay of gene function in lymphocyte development. Proc Natl Acad Sci U S A. 1993 May 15;90(10):4528–4532. doi: 10.1073/pnas.90.10.4528. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Chen J., Stewart V., Spyrou G., Hilberg F., Wagner E. F., Alt F. W. Generation of normal T and B lymphocytes by c-jun deficient embryonic stem cells. Immunity. 1994 Apr;1(1):65–72. doi: 10.1016/1074-7613(94)90010-8. [DOI] [PubMed] [Google Scholar]
  6. Chen W. S., Manova K., Weinstein D. C., Duncan S. A., Plump A. S., Prezioso V. R., Bachvarova R. F., Darnell J. E., Jr Disruption of the HNF-4 gene, expressed in visceral endoderm, leads to cell death in embryonic ectoderm and impaired gastrulation of mouse embryos. Genes Dev. 1994 Oct 15;8(20):2466–2477. doi: 10.1101/gad.8.20.2466. [DOI] [PubMed] [Google Scholar]
  7. Chen Z. F., Behringer R. R. twist is required in head mesenchyme for cranial neural tube morphogenesis. Genes Dev. 1995 Mar 15;9(6):686–699. doi: 10.1101/gad.9.6.686. [DOI] [PubMed] [Google Scholar]
  8. Conlon F. L., Barth K. S., Robertson E. J. A novel retrovirally induced embryonic lethal mutation in the mouse: assessment of the developmental fate of embryonic stem cells homozygous for the 413.d proviral integration. Development. 1991 Apr;111(4):969–981. doi: 10.1242/dev.111.4.969. [DOI] [PubMed] [Google Scholar]
  9. Deng C. X., Wynshaw-Boris A., Shen M. M., Daugherty C., Ornitz D. M., Leder P. Murine FGFR-1 is required for early postimplantation growth and axial organization. Genes Dev. 1994 Dec 15;8(24):3045–3057. doi: 10.1101/gad.8.24.3045. [DOI] [PubMed] [Google Scholar]
  10. Fischer K. D., Zmuldzinas A., Gardner S., Barbacid M., Bernstein A., Guidos C. Defective T-cell receptor signalling and positive selection of Vav-deficient CD4+ CD8+ thymocytes. Nature. 1995 Mar 30;374(6521):474–477. doi: 10.1038/374474a0. [DOI] [PubMed] [Google Scholar]
  11. Friedrich G., Soriano P. Promoter traps in embryonic stem cells: a genetic screen to identify and mutate developmental genes in mice. Genes Dev. 1991 Sep;5(9):1513–1523. doi: 10.1101/gad.5.9.1513. [DOI] [PubMed] [Google Scholar]
  12. Gu H., Marth J. D., Orban P. C., Mossmann H., Rajewsky K. Deletion of a DNA polymerase beta gene segment in T cells using cell type-specific gene targeting. Science. 1994 Jul 1;265(5168):103–106. doi: 10.1126/science.8016642. [DOI] [PubMed] [Google Scholar]
  13. Guillemot F., Nagy A., Auerbach A., Rossant J., Joyner A. L. Essential role of Mash-2 in extraembryonic development. Nature. 1994 Sep 22;371(6495):333–336. doi: 10.1038/371333a0. [DOI] [PubMed] [Google Scholar]
  14. Herrmann B. G., Kispert A. The T genes in embryogenesis. Trends Genet. 1994 Aug;10(8):280–286. doi: 10.1016/0168-9525(90)90011-t. [DOI] [PubMed] [Google Scholar]
  15. James R. M., Klerkx A. H., Keighren M., Flockhart J. H., West J. D. Restricted distribution of tetraploid cells in mouse tetraploid<==>diploid chimaeras. Dev Biol. 1995 Jan;167(1):213–226. doi: 10.1006/dbio.1995.1018. [DOI] [PubMed] [Google Scholar]
  16. Jonsson J., Carlsson L., Edlund T., Edlund H. Insulin-promoter-factor 1 is required for pancreas development in mice. Nature. 1994 Oct 13;371(6498):606–609. doi: 10.1038/371606a0. [DOI] [PubMed] [Google Scholar]
  17. Kühn R., Schwenk F., Aguet M., Rajewsky K. Inducible gene targeting in mice. Science. 1995 Sep 8;269(5229):1427–1429. doi: 10.1126/science.7660125. [DOI] [PubMed] [Google Scholar]
  18. Miettinen P. J., Berger J. E., Meneses J., Phung Y., Pedersen R. A., Werb Z., Derynck R. Epithelial immaturity and multiorgan failure in mice lacking epidermal growth factor receptor. Nature. 1995 Jul 27;376(6538):337–341. doi: 10.1038/376337a0. [DOI] [PubMed] [Google Scholar]
  19. Mombaerts P., Iacomini J., Johnson R. S., Herrup K., Tonegawa S., Papaioannou V. E. RAG-1-deficient mice have no mature B and T lymphocytes. Cell. 1992 Mar 6;68(5):869–877. doi: 10.1016/0092-8674(92)90030-g. [DOI] [PubMed] [Google Scholar]
  20. Mortensen R. M., Conner D. A., Chao S., Geisterfer-Lowrance A. A., Seidman J. G. Production of homozygous mutant ES cells with a single targeting construct. Mol Cell Biol. 1992 May;12(5):2391–2395. doi: 10.1128/mcb.12.5.2391. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Nagy A., Gócza E., Diaz E. M., Prideaux V. R., Iványi E., Markkula M., Rossant J. Embryonic stem cells alone are able to support fetal development in the mouse. Development. 1990 Nov;110(3):815–821. doi: 10.1242/dev.110.3.815. [DOI] [PubMed] [Google Scholar]
  22. Nagy A., Rossant J., Nagy R., Abramow-Newerly W., Roder J. C. Derivation of completely cell culture-derived mice from early-passage embryonic stem cells. Proc Natl Acad Sci U S A. 1993 Sep 15;90(18):8424–8428. doi: 10.1073/pnas.90.18.8424. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Puri M. C., Rossant J., Alitalo K., Bernstein A., Partanen J. The receptor tyrosine kinase TIE is required for integrity and survival of vascular endothelial cells. EMBO J. 1995 Dec 1;14(23):5884–5891. doi: 10.1002/j.1460-2075.1995.tb00276.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Rossant J., Nagy A. Genome engineering: the new mouse genetics. Nat Med. 1995 Jun;1(6):592–594. doi: 10.1038/nm0695-592. [DOI] [PubMed] [Google Scholar]
  25. Sauer B., Henderson N. Site-specific DNA recombination in mammalian cells by the Cre recombinase of bacteriophage P1. Proc Natl Acad Sci U S A. 1988 Jul;85(14):5166–5170. doi: 10.1073/pnas.85.14.5166. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Shalaby F., Rossant J., Yamaguchi T. P., Gertsenstein M., Wu X. F., Breitman M. L., Schuh A. C. Failure of blood-island formation and vasculogenesis in Flk-1-deficient mice. Nature. 1995 Jul 6;376(6535):62–66. doi: 10.1038/376062a0. [DOI] [PubMed] [Google Scholar]
  27. Shinkai Y., Rathbun G., Lam K. P., Oltz E. M., Stewart V., Mendelsohn M., Charron J., Datta M., Young F., Stall A. M. RAG-2-deficient mice lack mature lymphocytes owing to inability to initiate V(D)J rearrangement. Cell. 1992 Mar 6;68(5):855–867. doi: 10.1016/0092-8674(92)90029-c. [DOI] [PubMed] [Google Scholar]
  28. Sibilia M., Wagner E. F. Strain-dependent epithelial defects in mice lacking the EGF receptor. Science. 1995 Jul 14;269(5221):234–238. doi: 10.1126/science.7618085. [DOI] [PubMed] [Google Scholar]
  29. Tarakhovsky A., Turner M., Schaal S., Mee P. J., Duddy L. P., Rajewsky K., Tybulewicz V. L. Defective antigen receptor-mediated proliferation of B and T cells in the absence of Vav. Nature. 1995 Mar 30;374(6521):467–470. doi: 10.1038/374467a0. [DOI] [PubMed] [Google Scholar]
  30. Threadgill D. W., Dlugosz A. A., Hansen L. A., Tennenbaum T., Lichti U., Yee D., LaMantia C., Mourton T., Herrup K., Harris R. C. Targeted disruption of mouse EGF receptor: effect of genetic background on mutant phenotype. Science. 1995 Jul 14;269(5221):230–234. doi: 10.1126/science.7618084. [DOI] [PubMed] [Google Scholar]
  31. Tsai F. Y., Keller G., Kuo F. C., Weiss M., Chen J., Rosenblatt M., Alt F. W., Orkin S. H. An early haematopoietic defect in mice lacking the transcription factor GATA-2. Nature. 1994 Sep 15;371(6494):221–226. doi: 10.1038/371221a0. [DOI] [PubMed] [Google Scholar]
  32. Weinstein D. C., Ruiz i Altaba A., Chen W. S., Hoodless P., Prezioso V. R., Jessell T. M., Darnell J. E., Jr The winged-helix transcription factor HNF-3 beta is required for notochord development in the mouse embryo. Cell. 1994 Aug 26;78(4):575–588. doi: 10.1016/0092-8674(94)90523-1. [DOI] [PubMed] [Google Scholar]
  33. Weiss M. J., Orkin S. H. In vitro differentiation of murine embryonic stem cells. New approaches to old problems. J Clin Invest. 1996 Feb 1;97(3):591–595. doi: 10.1172/JCI118454. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Wilson V., Manson L., Skarnes W. C., Beddington R. S. The T gene is necessary for normal mesodermal morphogenetic cell movements during gastrulation. Development. 1995 Mar;121(3):877–886. doi: 10.1242/dev.121.3.877. [DOI] [PubMed] [Google Scholar]
  35. Wurst W., Auerbach A. B., Joyner A. L. Multiple developmental defects in Engrailed-1 mutant mice: an early mid-hindbrain deletion and patterning defects in forelimbs and sternum. Development. 1994 Jul;120(7):2065–2075. doi: 10.1242/dev.120.7.2065. [DOI] [PubMed] [Google Scholar]
  36. Yamaguchi T. P., Harpal K., Henkemeyer M., Rossant J. fgfr-1 is required for embryonic growth and mesodermal patterning during mouse gastrulation. Genes Dev. 1994 Dec 15;8(24):3032–3044. doi: 10.1101/gad.8.24.3032. [DOI] [PubMed] [Google Scholar]
  37. Zhang R., Alt F. W., Davidson L., Orkin S. H., Swat W. Defective signalling through the T- and B-cell antigen receptors in lymphoid cells lacking the vav proto-oncogene. Nature. 1995 Mar 30;374(6521):470–473. doi: 10.1038/374470a0. [DOI] [PubMed] [Google Scholar]
  38. Zhou X., Sasaki H., Lowe L., Hogan B. L., Kuehn M. R. Nodal is a novel TGF-beta-like gene expressed in the mouse node during gastrulation. Nature. 1993 Feb 11;361(6412):543–547. doi: 10.1038/361543a0. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES