Cell types are typically defined by expression of a unique combination of genes, rather than a single gene. Intersectional methods therefore become crucial to selectively access these cells for higher resolution fate mapping and functional manipulations. Here, we discuss one such intersectional method. Two recombinase systems (Cre/loxP and Flp/FRT) work together to remove a double STOP cassette and thereby activate expression of a target transgene solely in cells defined by a particular pairwise combination of driver genes. Depending on the nature of the target transgene, this strategy can be used to deliver cell-lineage tracers, sensors, and/or effector molecules to highly selective cell types in vivo. In this chapter, we discuss concepts, reagents, and methods underlying this intersectional approach and encourage consideration of various intersectional and binary methods for accessing uniquely defined cell subsets in the mouse.
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