Conditional mutagenesis in mice with heat shock promoter-driven cre transgenes

To explore the potential of a simple and rapid approach for ubiquitous cond itional gene disruption, we have generated Cre-producer mouse transgenic li nes (Hs-cre1, 6 and 7) expressing a recombinase transgene (cre) from a heat shock gene promoter and tested their performance in Cre-mediated excision of target DNA in crosses with Cre-responder strains carrying loxP-modified alleles of the genes encoding the Huntington's disease gene homolog (Hdh), the epidermal growth factor receptor (Egfr), and the type 1 insulin-like gr owth factor receptor (Igf1r). Analyses of progeny possessing various transg ene/reporter combinations showed that CM expression can occur without heat shock in early embryos, but this constitutive transcription is stochastic a nd transgene dependent. Thus, Hs-cre1 behaves predominantly as a "deleter" strain, since the majority of progeny (similar to 70-85%) exhibit complete recombination, regardless of reporter locus. Lines Hs-cre6 and Hs-cre7, how ever, function successfully as "mosaicking" strains because, in addition to two extreme classes of progeny with 0% or 100% recombination, they generat e an intermediate class of mosaics exhibiting various degrees of partial DN A excision. Notably, the frequency of offspring in each class varies betwee n reporters, but mosaic embryos are consistently obtained in adequate numbe rs (similar to 30-60%). The Hs-cre6 transgene is also inducible and can be used to introduce mosaicism into adult tissues at preselected developmental times by heat shock treatment of mice with 0% recombination in tail DNA. B y bypassing the lethality resulting from some gene knockouts, mosaic embryo s and mice make particular mutational analyses possible and are also very u seful for the identification of cell lineage-specific gene functions.