A "TetOP-Cre flip-in plasmid" (containing a splice acceptor-polyA sequence and the tetracycline operator elements (tet)) fused to a CMV minimal promoter upstream of a cre recombinase cassette) was used to treat ES cells containing an FRT-PGK-neo-hygro-FRT cassette inserted into the 3' UTR of the Col1a1 locus (Col1a1tm13(neo/hygro)Jae). The "flip-in" vector was coinjected with a Flpe-encoding plasmid so that flippase-mediated recombination inserted the tetO-cre sequence into the Col1a1 3' UTR. The Col1a1tm13(neo/hygro)Jae ES cells also contain the Gt(ROSA)26Sortm1(rtTA*M2)Jae allele. The twice-targeted ES cells were used to generate chimeras and germline animals. By treating this mouse line with doxycycline, rtTA*M2 binds the TetOP promoter and cre is expressed.