Effect of deletion of Impdh2 on gene expression in the forlimbs from E12.5 embryos and osteoclasts (OCs). Effect of deletion of Impdh2 on gene expression in the forlimbs from E12.5 embryos and osteoclasts (OCs)

Many factors are essential for skeletal development and homeostaisis. Here we report that inosine monophosphate dehydrogenase type II (Impdh2) is a key positive regulator for limb development and bone resorption. Deletion of Impdh2 in limb mesenchymal progenitors impaired the differentiation of mesenchymal cells into chondrocyte. Meanwhile, deletion of Impdh2 in osteoclast precursors results in mice an osteopetrotic phenotype via suppressing osteoclast differentiation. Our results reveal a previously unrecognized role of Impdh2 on skeletal development and homeostasis. Overall design: To investigate the physiological significance and function of Impdh2 in the regulation of limb development and osteoclastogenesis, we respectively generated limb mesenchymal progenitors and myeloid lineage cells, i.e., osteoclast precursors specific Impdh2 knockout mice (Prx-cKO and LysM-cKO mice). We then performed gene expression profiling analysis using data obtained from RNA-seq from forelimbs of Impdh2 WT and Prx-cKO mice embryos at E12.5, and osteoclasts of Impdh2 WT and LysM-cKO mice.

骨骼发育与体内稳态的维持依赖诸多关键因子。本研究报道，II型次黄嘌呤核苷酸脱氢酶（inosine monophosphate dehydrogenase type II，Impdh2）是肢体发育与骨吸收过程的关键正向调控因子。在肢体间充质祖细胞中敲除Impdh2，会阻碍间充质细胞向软骨细胞的分化进程。与此同时，在破骨细胞前体细胞中敲除Impdh2，会通过抑制破骨细胞分化使小鼠出现骨硬化症表型。本研究结果揭示了Impdh2此前未被认知的骨骼发育与稳态调控功能。整体实验设计：为探究Impdh2在肢体发育与破骨细胞生成调控中的生理意义与功能，我们分别构建了肢体间充质祖细胞特异性敲除Impdh2的小鼠（Prx-cKO小鼠）以及髓系细胞（即破骨细胞前体细胞）特异性敲除Impdh2的小鼠（LysM-cKO小鼠）。随后，我们通过对E12.5天的Impdh2野生型与Prx-cKO小鼠胚胎前肢组织、以及Impdh2野生型与LysM-cKO小鼠破骨细胞的RNA-seq数据进行基因表达谱分析。