Translational Control of Sox9 RNA by mTORC1 Contributes to Skeletogenesis
| Autor: | Manami Hiraiwa, Makoto Kitabatake, Katsuyuki Kaneda, Takayuki Manabe, Gyujin Park, Takashi Iezaki, Yuka Kitaguchi, Kazuya Fukasawa, Mutsuhito Ohno, Eiichi Hinoi, Takashi Kanayama, Yuki Onishi, Tetsuhiro Horie, Yuka Nakamura, Yasuhito Ishigaki, Kakeru Ozaki |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Cell type Transgene translation Gene Expression Mice Transgenic SOX9 mTORC1 Mechanistic Target of Rapamycin Complex 1 Biology Biochemistry Article Mice 03 medical and health sciences Osteogenesis Genetics Animals lcsh:QH301-705.5 undifferentiated mesenchymal cells Skeleton lcsh:R5-920 Gene knockdown Mesenchymal stem cell RNA Cell Differentiation SOX9 Transcription Factor Cell Biology Phenotype Cell biology 030104 developmental biology lcsh:Biology (General) Protein Biosynthesis biological phenomena cell phenomena and immunity lcsh:Medicine (General) Sox9 Developmental Biology |
| Zdroj: | Stem Cell Reports Stem Cell Reports, Vol 11, Iss 1, Pp 228-241 (2018) |
| ISSN: | 2213-6711 |
| DOI: | 10.1016/j.stemcr.2018.05.020 |
| Popis: | Summary 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. Highlights • 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. |
| Databáze: | OpenAIRE |
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