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Mouse mutants from chemically mutagenized embryonic stem cells.

The drive to characterize functions of human genes on a global scale has stimulated interest in large-scale generation of mouse mutants. Conventional germ-cell mutagenesis with N-ethyl-N-nitrosourea (ENU) is compromised by an inability to monitor mutation efficiency, strain and interlocus variation in mutation induction, and extensive husbandry requirements. To overcome these obstacles and develop new methods for generating mouse mutants, we devised protocols to generate germline chimaeric mice from embryonic stem (ES) cells heavily mutagenized with ethylmethanesulphonate (EMS). Germline chimaeras were derived from cultures that underwent a mutation rate of up to 1 in 1,200 at the Hprt locus (encoding hypoxanthine guanine phosphoribosyl transferase). The spectrum of mutations induced by EMS and the frameshift mutagen ICR191 was consistent with that observed in other mammalian cells. Chimaeras derived from ES cells treated with EMS transmitted mutations affecting several processes, including limb development, hair growth, hearing and gametogenesis. This technology affords several advantages over traditional mutagenesis, including the ability to conduct shortened breeding schemes and to screen for mutant phenotypes directly in ES cells or their differentiated derivatives.

Pubmed ID: 10700192


  • Munroe RJ
  • Bergstrom RA
  • Zheng QY
  • Libby B
  • Smith R
  • John SW
  • Schimenti KJ
  • Browning VL
  • Schimenti JC


Nature genetics

Publication Data

March 7, 2000

Associated Grants

  • Agency: NCI NIH HHS, Id: CA34196
  • Agency: NICHD NIH HHS, Id: F32 HD008441-02
  • Agency: NIGMS NIH HHS, Id: GM45415
  • Agency: NICHD NIH HHS, Id: HD07065
  • Agency: NCI NIH HHS, Id: P30 CA034196-159007
  • Agency: NIDCD NIH HHS, Id: R01 DC004301
  • Agency: NIDCD NIH HHS, Id: R01 DC004301-01
  • Agency: NIDCD NIH HHS, Id: R01 DC005827
  • Agency: NIDCD NIH HHS, Id: R01 DC005827-01
  • Agency: NIGMS NIH HHS, Id: R01 GM045415
  • Agency: NIGMS NIH HHS, Id: R01 GM045415-12
  • Agency: NIDCD NIH HHS, Id: R03 DC004376
  • Agency: NIDCD NIH HHS, Id: R03 DC004376-01A1
  • Agency: Howard Hughes Medical Institute, Id:

Mesh Terms

  • Abnormalities, Drug-Induced
  • Abnormalities, Multiple
  • Animals
  • Bone and Bones
  • Chimera
  • Ethyl Methanesulfonate
  • Ethylnitrosourea
  • Female
  • Genes, Lethal
  • Hypoxanthine Phosphoribosyltransferase
  • Limb Deformities, Congenital
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Mutant Strains
  • Mutagenesis
  • Mutagens
  • Point Mutation
  • RNA Splicing
  • Retina
  • Stem Cells
  • Testis