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The functions of mTOR complex subunits Rictor and Raptor in myelination

Final Report Summary - MTORC IN MYELINATION (The functions of mTOR complex subunits Rictor and Raptor in myelination)

Myelination of axons allows rapid propagation of action potentials along the nerve, and is essential for normal function of the nervous system. Diseases affecting myelinating cells, like multiple sclerosis and peripheral neuropathies, have to date very limited forms of treatment. Thus, understanding the molecular basis of myelination is of fundamental importance to provide the foundation for therapeutic solutions to these disabling diseases.

Mammalian target of rapamycin (mTOR) is a central regulator of cell growth and metabolism, and is intimately linked with PI3K-Akt signaling. The PI3K-Akt pathway on the other hand is a major player involved in myelination, integrating critical signals mainly from growth factors and the extra-cellular environment. However, very little is known about the role of mTOR signaling in regulating Schwann cell biology and myelination in the PNS.

In this project, we have been examining the functional role of mTOR signaling in PNS myelination by conditionally deleting Raptor or Rictor (critical subunits of the two mTOR-containing complexes mTORC1 and mTORC2, respectively) in developing Schwann cells, with the objective to mechanistically understand how mTOR signalling is regulating myelination. We have analysed nerves from mice at different time points of development to morphologically and biochemically determine how deficient mTOR signalling affects myelination. We have furthermore carried out in vitro analysis on primary rat Schwann cells to complement our in vivo findings. Our analysis shows that nerves lacking Raptor have impaired myelination, both during development and in regeneration after injury. Our results also show that signalling pathways downstream of mTOR are severely affected in our knock-out mice, resulting in defective myelin. Our results are now being prepared for publication.