SUSTAINED SOMATIC GENE INACTIVATION BY VIRAL TRANSFER OF CRE RECOMBINASE

Transgenic and knockout mice have proven invaluable tools for analyzin g physiologically relevant functions of numerous genes. In some cases, however, pleiotropic effects that result from a variable requirement for a particular gene in different tissues, cell types, or stages of e mbryonic development may complicate the analysis due to a complex phen otype or embryonic lethality, The loxP/Cre-mediated recombination syst em, which allows tissue-specific gene targeting in the mouse, can be u sed to overcome these problems, A limitation of current methods is tha t a mouse carrying a loxP-tagged gene must be crossed with a transgeni c mouse expressing the Cre recombinase in an appropriate tissue to obt ain the desired gene rearrangement. We have used recombinant adenoviru s carrying the Cre recombinase to induce virtually quantitative somati c cell gene disruption in the liver. The targeted gene was the multifu nctional low-density lipoprotein receptor-related protein (LRP), a cel l surface receptor for alpha(2)-macroglobulin and other ligands, Trans ient expression of Cre following adenoviral infection produced the pre dicted gene rearrangement, functionally inactivating LRP in the liver. Rearrangement occurred within 6 days after infection and remained sta ble for at least 28 days, the results demonstrate the suitability of a denoviral Cre gene transfer to induce long-term, quantitative, and tem porally controlled gene disruption in the mouse.