Mutant Mice from the Large-scale Mutagenesis Project at the RIKEN GSC

The ENU-induced mutant mice developed by the RIKEN GSC are distributed by the RIKEN BRC. The mutant strains are supplied as live mice or as straws of frozen sperms.

 

Introduction
The human and mouse genome projects have revealed that the genome of the two species are highly similar. Mouse models of human diseases, therefore, are essential tools for future studies of the biological function of genes. They are also useful for developing novel therapeutic drugs and diagnosing human diseases. In order to generate novel mouse models for human disease, transgenesis and gene-targeting technologies have been used for previously cloned genes in a “gene-driven” approach. Another systematic approach using ENU mutagenesis has been undertaken to recover a large number of mutations through a large-scale mutagenesis project in the RIKEN GSC. The goals of their “phenotype-driven” approach are twofold: to generate enough mutants to encompass the entire mouse genome in order to provide resources for studying gene function; and to develop mouse models for human diseases.
In their mutagenesis project, the RIKEN GSC uses N-ethyl-N-nitrosourea (ENU) as an effective mutagen. It induces mutations 1000 times more frequently in male spermatogonial germ cells than occur spontaneously. ENU is one of the most effective alkylating mutagens and it is known to randomly induce point mutations. Since most human genetic diseases are caused by partial loss of the gene function due to point mutations, ENU-induced mouse mutants can serve as good models for human diseases.
Well-established inbred strains are used for mutagenesis. The ENU-treated males (G0) are crossed to/with wild-type females to generate the first generation of offspring (G1). Dominant mutations are recovered by systematic phenotype screens in the G1 mice. Recessive mutations are recovered as follows: The G1 males are mated to obtain females of the second generation (G2). The G2 females are then backcrossed with the original paternal G1 male. Mice homozygous for recessive mutations are generated in the third generation (G3). Recessive mutations are recovered by careful and thorough phenotype screens in the G3 mice. All mutant mice discovered through this project are frozen-stored as sperm of the G1 males for future use.

Reference : Mamm. Genome, 15(5):404-11 (2004).



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