Translational Control of Sox9 RNA by mTORC1 Contributes to Skeletogenesis

Area of Science:

• Molecular Biology
• Developmental Biology
• Cellular Signaling

Background:

• The mechanistic/mammalian target of rapamycin complex 1 (mTORC1) is a key regulator of cellular functions.
• Previous studies have explored mTORC1's role in skeletogenesis, but its precise mechanisms remain incompletely understood.

Purpose of the Study:

• To elucidate the critical role of the mTORC1/4E-BPs/SOX9 axis in regulating mammalian skeletogenesis.
• To investigate the specific mechanisms by which mTORC1 influences skeletal development, particularly in undifferentiated mesenchymal cells.

Main Methods:

• Inactivation of Raptor, an mTORC1 component, in mouse limb buds.
• Analysis of cartilage and bone formation in genetically modified mice.
• Investigating the translational control of SOX9 RNA by mTORC1 via 4E-BPs.
• Rescue experiments involving SOX9 introduction or 4E-BP1/2 knockdown.

Main Results:

• Inactivation of mTORC1 in limb buds led to significant defects in cartilage and bone development.
• mTORC1 was found to selectively control SOX9 RNA translation through the inhibition of 4E-BPs.
• Restoration of SOX9 levels or inhibition of 4E-BP1/2 rescued mesenchymal condensation defects.
• SOX9 transgene introduction rescued skeletal growth deficiencies in Raptor-deficient mice.

Conclusions:

• The mTORC1 pathway plays a critical role in mammalian skeletogenesis.
• This regulation is achieved, at least partly, through the translational control of SOX9 RNA by mTORC1.
• The mTORC1/4E-BPs/SOX9 axis is essential for skeletal development in undifferentiated mesenchymal cells.