The directed introduction of null mutations into defined genes has proven invaluable in elucidating gene function in a variety of experimental organisms. In the last decade or so this approach has been extended to mice (1 ) by the combined use of homologous recombination in murine embryonic stem (ES) cells to precisely target a mutation to a desired gene and subsequent derivation of mice carrying the targeted gene alteration from the genetically manipulated ES cells (e.g., by injection of gene- modified ES cells into blastocysts with subsequent germline transmission). In most instances null, or knockout (KO), mutations have been generated in mice by either simple insertion of aneoselectable marker in the target gene orneoinsertion coupled with deletion of a critical region of the target gene. Targeted null mutations in a gene of interest, however, can lead to embryonic lethality in mice, thus obscuring the particular role of that gene in a target tissue or in the adult.
