The DTR system is a novel cell lineage ablation system based on the expression of the diphtheria toxin receptor (DTR) in transgenic mice and the administration of diphtheria toxin (DT). By knocking in the DTR gene at the target gene locus (usually a marker gene), selective ablation of cells expressing specific genes can be achieved ^[1]. When the target gene begins to be expressed in cells of mice that have been transgenically modified to express DTR, injection of DT can induce the death of these cells, resulting in apoptosis.

The core of the DTR system is the toxic effect of DT, an exotoxin that, once it enters cells via its receptor, can catalyze the transfer of the ADP-ribosyl moiety from NAD+ to elongation factor 2 (EF-2) due to the ADP-ribosyltransferase activity present in its C-domain, resulting in EF-2 inactivation and inhibition of protein synthesis, ultimately leading to cell death ^[2]. Due to species differences in the sequence of the DTR gene, the diphtheria toxin receptor in mice cannot bind to DT ^[3]. This can be overcome by knocking in the primate DTR gene into the mouse genome, allowing specific cells to express DTR and enabling DT to enter specific cells upon administration, and resulting in cell-specific ablation.

RC-LR-DTR mice are generated by combining the DTR system with the Cre-loxP and Dre-rox conditional recombinase systems. When these mice are crossed with Cre and Dre mice, DTR can be expressed specifically in tissues to induce tissue- and cell-specific ablation. Heterozygous RC-LR-DTR mice are viable and fertile, and homozygous RC-LR-DTR mice are also viable.