Division of Molecular Immunology, Medical Institute of Bioregulation, Kyushu University, Japan.
Department of Molecular Immunology, Research Institute for Microbial Diseases.
Int Immunol. 2017 Dec 18;29(10):479-485. doi: 10.1093/intimm/dxx056.
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-/-Erk2flox/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 a CD3ε-deficient background. In addition, adoptive transfer of bone marrow cells from Erk∆CD2-Cre mice to wild-type 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 an 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, G., Gallardo, D. L., Li, W. et al. 2017. Unexpected cartilage phenotype in CD4-Cre-conditional SOS-deficient mice. Front. Immunol. 8:343; Wehenkel, M., Corr, M., Guy, C. S. et al. 2017. Extracellular signal-regulated kinase signaling in CD4-expressing cells inhibits osteochondromas. Front. Immunol. 8:482). Together with these reports, our study suggests that an unexpected link exists between T-like cell and chondrocyte lineages during ontogeny.
谱系特异性 Cre Tg 小鼠被广泛用于以组织特异性方式描绘基因的功能。已经开发了几种 T 细胞特异性启动子盒；然而，这些启动子在非 T 细胞中的活性尚未得到广泛研究。在这里，我们报告说，通过生成 CD2-Cre × Erk1-/-Erk2flox/flox（Erk∆CD2-Cre）小鼠，CD2-Cre 介导的 Erk 蛋白缺失导致软骨过度增生。组织学分析表明，这种异常是由软骨细胞的异常增生引起的。这种软骨瘤的形成不需要缺乏 Erk 的 T 细胞的存在，因为在 CD3ε 缺陷背景下缺乏 T 细胞时也观察到了同样的情况。此外，将来自 Erk∆CD2-Cre 小鼠的骨髓细胞过继转移到野生型受体中不会导致软骨瘤形成，这表明缺乏 Erk 的非免疫细胞是造成这种异常的原因。通过使用 ROSA26-STOP-RFP 等位基因追踪 Cre 表达的组织，我们发现软骨瘤发出 RFP 荧光，表明在 Erk∆CD2-Cre 小鼠中，功能性 Cre 表达在过度增生的软骨细胞中。此外，在 Erk 充分表达的背景下也发现了 RFP+软骨细胞，尽管没有异常生长。这些结果表明，CD2 驱动的 Cre 在软骨细胞中的意外表达会产生缺乏 Erk 的软骨细胞，导致过度增生的软骨形成。最近，两份独立的报告显示，CD4-Cre 介导的 Ras-Erk 信号缺失导致类似的异常软骨形成（Guittard，G.，Gallardo，D. L.，Li，W. 等人。2017. CD4-Cre 条件性 SOS 缺陷小鼠中意外的软骨表型。Front. Immunol. 8:343；Wehenkel，M.，Corr，M.，Guy，C. S. 等人。2017. CD4 表达细胞中的细胞外信号调节激酶信号抑制骨软骨瘤。Front. Immunol. 8:482）。结合这些报告，我们的研究表明，在个体发生过程中，T 样细胞和软骨细胞谱系之间存在意外的联系。
