Translational Control of Sox9 RNA by mTORC1 Contributes to Skeletogenesis

Abstract

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