Spontaneous chondroma formation in CD2-Cre-driven Erk-deficient Mice

Abstract

Lineage-specific Cre Tg mice are widely used to delineate the functions of genes in a tissue-specific manner. Several T cell-specific promoter cassettes have been developed, however, the activities of those promoters in non-T cells have not been investigated extensively. Here, we report that CD2-Cre-mediated deletion of Erk proteins by generating CD2-Cre × Erk1^–/–Erk2^flox/flox (Erk^∆CD2-Cre) mice results in abnormal cartilage hyperplasia. Histological analysis revealed that this abnormality is caused by aberrant hyperplasia of chondrocytes. The presence of Erk-deficient T cells is not required for this chondroma formation, as it was similarly observed in the absence of T cells in CD3-deficient background. In addition, adoptive transfer of bone marrow cells from Erk^∆CD2-Cre mice to WT recipients did not cause chondroma formation, suggesting that Erk-deficient non-immune cells are responsible for this abnormality. By tracing Cre-expressed tissues using a ROSA26-STOP-RFP allele, we found that the chondroma emitted RFP fluorescence, indicating that functional Cre is expressed in hyperplastic chondrocytes in Erk^∆CD2-Cre mice. Furthermore, RFP⁺ chondrocytes were also found in Erk-sufficient background, albeit without aberrant growth. These results suggest that unexpected expression of CD2-driven Cre in chondrocytes generates Erk-deficient chondrocytes, resulting in hyperplastic cartilage formation. Recently, two independent reports showed that CD4-Cre-mediated Ras-Erk signaling ablation led to similar abnormal cartilage formation (Guittard, et al, Front. Immunol., 2017; Wehenkel, et al, Front. Immunol., 2017). Together with these reports, our study suggests that an unexpected link exists between T cell and chondrocyte lineages during ontogeny.