Translational Control of Sox9 RNA by mTORC1 Contributes to Skeletogenesis.
Translational Control of Sox9 RNA by mTORC1 Contributes to Skeletogenesis.
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DOI：
10.1016/j.stemcr.2018.05.020
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发表时间：
2018-07-10
影响因子：
5.9
通讯作者：
Hinoi E
中科院分区：
文献类型：
--
作者：
Iezaki T;Horie T;Fukasawa K;Kitabatake M;Nakamura Y;Park G;Onishi Y;Ozaki K;Kanayama T;Hiraiwa M;Kitaguchi Y;Kaneda K;Manabe T;Ishigaki Y;Ohno M;Hinoi E
雷帕霉素复合体1的机械/哺乳动物靶点(MTORC1)在不同类型的细胞中调节细胞功能。虽然mTORC1在骨骼形成中的作用已经被研究过，但在这里，我们发现mTORC1/4E-BPS/SOX9轴通过其在未分化的间充质细胞中的表达而在调节骨骼形成中发挥关键作用。在间充质冷凝之前，肢芽中mTORC1的一种成分Raptor被灭活，导致软骨和骨骼的显著丧失。从机制上讲，我们证明了mTORC1通过抑制4e-bps选择性地控制Sox9的RNA翻译，Sox9含有5‘末端的寡嘧啶基序。事实上，在未分化的间充质细胞中引入Sox9或敲除4E-BP1/2显著地挽救了在Raptor缺陷小鼠中观察到的凝集缺陷。此外，Sox9转基因的引入挽救了Raptor基因缺陷小鼠骨骼生长缺陷的表型。这些发现突显了mTORC1在哺乳动物骨骼形成中的关键作用，至少部分是通过对Sox9 RNA的翻译控制。MTORC1调控成骨祖细胞和软骨细胞中的骨形成，mTORC1/4E-BPS级联调控Sox9 RNA的翻译SOX9是mTORC1在体内调控骨形成的关键介体。通过在体内未分化间充质细胞中的表达，证明了mTORC1/SOX9轴在骨骼发育中具有重要作用。此外，他们发现mTORC1/4E-BPS级联调控未分化间充质细胞中Sox9 RNA的翻译，突显了mTORC1/4E-BPS/SOX9轴在调控哺乳动物骨骼形成中的关键作用。
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. mTORC1 controls skeletogenesis both in skeletogenic progenitors and in chondrocytes mTORC1/4E-BPs cascade regulates the translation of Sox9 RNA SOX9 is a critical mediator in the control of skeletogenesis by mTORC1 in vivo Iezaki et al. demonstrated that the mTORC1/SOX9 axis has essential roles in skeletal development through its expression in undifferentiated mesenchymal cells in vivo. Moreover, they identified that mTORC1/4E-BPs cascade regulates the translation of Sox9 RNA in undifferentiated mesenchymal cells, highlighting a critical role of mTORC1/4E-BPs/SOX9 axis in regulating mammalian skeletogenesis.
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影响因子：
2.9
作者：
Lefebvre V;Dvir-Ginzberg M
通讯作者：
Dvir-Ginzberg M
影响因子：
21.3
作者：
通讯作者：
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各种各样的癌症相关MTOR突变是过度激活的，可以预测雷帕霉素的敏感性。
影响因子：
28.2
作者：
Grabiner BC;Nardi V;Birsoy K;Possemato R;Shen K;Sinha S;Jordan A;Beck AH;Sabatini DM
通讯作者：
Sabatini DM
影响因子：
9.2
作者：
Lin X;Zhang Y;Liu L;McKeehan WL;Shen Y;Song S;Wang F
通讯作者：
Wang F
影响因子：
10.5
作者：
Akiyama, H;Chaboissier, MC;de Crombrugghe, B
通讯作者：
de Crombrugghe, B