Laboratory of Molecular Pharmacology, Division of Pharmaceutical Sciences, Kanazawa University Graduate School, Kakuma-machi, Kanazawa, Ishikawa 920-1192, Japan; Venture Business Laboratory, Organization of Frontier Science and Innovation, Kanazawa University, Kanazawa, Ishikawa 920-1192, Japan.
Laboratory of Molecular Pharmacology, Division of Pharmaceutical Sciences, Kanazawa University Graduate School, Kakuma-machi, Kanazawa, Ishikawa 920-1192, Japan.
Stem Cell Reports. 2018 Jul 10;11(1):228-241. doi: 10.1016/j.stemcr.2018.05.020. Epub 2018 Jun 28.
The mechanistic/mammalian target of rapamycin complex 1 (mTORC1) regulates cellular function in various cell types. Although the role of mTORC1 in skeletogenesis has been investigated previously, here we show a critical role of mTORC1/4E-BPs/SOX9 axis in regulating skeletogenesis through its expression in undifferentiated mesenchymal cells. Inactivation of Raptor, a component of mTORC1, in limb buds before mesenchymal condensations resulted in a marked loss of both cartilage and bone. Mechanistically, we demonstrated that mTORC1 selectively controls the RNA translation of Sox9, which harbors a 5' terminal oligopyrimidine tract motif, via inhibition of the 4E-BPs. Indeed, introduction of Sox9 or a knockdown of 4E-BP1/2 in undifferentiated mesenchymal cells markedly rescued the deficiency of the condensation observed in Raptor-deficient mice. Furthermore, introduction of the Sox9 transgene rescued phenotypes of deficient skeletal growth in Raptor-deficient mice. These findings highlight a critical role of mTORC1 in mammalian skeletogenesis, at least in part, through translational control of Sox9 RNA.
机械性/哺乳动物雷帕霉素靶蛋白复合物 1（mTORC1）调节各种细胞类型的细胞功能。尽管之前已经研究了 mTORC1 在骨骼发生中的作用，但我们在这里展示了 mTORC1/4E-BPs/SOX9 轴通过在未分化的间充质细胞中的表达在调节骨骼发生中的关键作用。在间充质凝聚之前，Raptor（mTORC1 的一个组成部分）在肢芽中的失活导致软骨和骨的明显丢失。从机制上讲，我们证明 mTORC1 通过抑制 4E-BPs 选择性地控制 Sox9 的 RNA 翻译，Sox9 含有 5'端寡嘧啶序列基序。事实上，在未分化的间充质细胞中引入 Sox9 或敲低 4E-BP1/2 可显著挽救 Raptor 缺陷型小鼠中观察到的凝聚缺陷。此外，Sox9 转基因的引入挽救了 Raptor 缺陷型小鼠中骨骼生长不足的表型。这些发现强调了 mTORC1 在哺乳动物骨骼发生中的关键作用，至少部分是通过 Sox9 RNA 的翻译控制。
