Translational Control of Sox9 RNA by mTORC1 Contributes to Skeletogenesis

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.

Keywords: Sox9; mTORC1; translation; undifferentiated mesenchymal cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation / genetics
  • Gene Expression
  • Mechanistic Target of Rapamycin Complex 1 / metabolism*
  • Mice
  • Mice, Transgenic
  • Osteogenesis / genetics*
  • Phenotype
  • Protein Biosynthesis*
  • SOX9 Transcription Factor / genetics*
  • SOX9 Transcription Factor / metabolism
  • Skeleton / embryology
  • Skeleton / metabolism*


  • SOX9 Transcription Factor
  • Sox9 protein, mouse
  • Mechanistic Target of Rapamycin Complex 1