Elimination of background recombination: somatic induction of Cre by combined transcriptional regulation and hormone binding affinity.

Somatically inducible Cre lines are used extensively to study gene function. However, a background level of spontaneous recombination due to unregulated expression of Cre is particularly confounding for cancer models in which following the pathogenesis of the disease requires the introduction of sporadic mutations that are monitored over time. In three transgenic mouse lines, two with Cre activity controlled at the transcriptional level (Ahcre, Mx1cre), and one controlled at the protein level (R26creER(T)), we have identified sporadic recombination at the R26R reporter locus in multiple tissues. Detailed analysis of the intestinal epithelium suggests that recombination can occur both during development and as an ongoing process in adult life. Here we present a new inducible Cre transgenic line, AhcreER(T), in which control of Cre activity is regulated at two levels: by transcriptional control of the Ah promoter and by a requirement for Tamoxifen binding. There is no detectable background intestinal recombination in adult AhcreER(T) mice on the R26R background. Inducible and dose-dependent recombination can be achieved by a single combined treatment with beta-napthoflavone and Tamoxifen.