Identifying the variables that drive tamoxifen-independent CreERT2 recombination: Implications for microglial fate mapping and gene deletions.

Ligand-dependent Cre recombinases such as the CreERT2 system allow for tamoxifen-inducible Cre recombination. Important examples are the Cx3cr1-CreERT2 and Sall1-CreERT2 lines that are widely used for fate mapping and gene deletion studies of brain macrophages. Our results now show that both CreERT2 lines can exhibit a high rate of tamoxifen-independent "leaky" excision with some reporter strains, while this is not observed with others. We suggest that this disparity is determined by the length of the floxed transcriptional STOP cassette that is incorporated in the various reporter lines. In addition, the rate of spontaneous recombination was also determined by the CreERT2 expression levels and the longevity of the CreERT2-expressing cells. The implications of these results are discussed in the context of fate mapping and inducible gene deletion studies in macrophages and microglia.