MTORC IN MYELINATION

The functions of mTOR complex subunits Rictor and Raptor in myelination

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 Obiettivo del progetto (Objective)

'Understanding the molecular basis of myelination, and the nature of the cells that achieve myelination, is of fundamental importance for both basic and clinical neuroscience. Detailed insights into these processes are likely to provide the foundation for therapeutic approaches to diseases affecting myelinating cells, like Multiple sclerosis in the central nervous system (CNS) and Peripheral Neuropathies in the peripheral nervous system (PNS). The host lab has shown that integrin-mediated signals derived from the extracellular matrix together with growth factor signaling via tyrosine kinase receptors are critical for the correct development of myelinating cells and their interaction with neurons. Particularly critical signals integrators are ILK (integrin-linked kinase), as well as the small RhoGTPases Rac1 and Cdc42. Complementary lines of research point to a connected critical role of the PI3K/Akt pathway. The two mTOR-containing complexes 1 (mTORC1) and 2 (mTORC2) are major regulators of these signaling pathways. In this project, we will examine the functional role of mTORC1 and mTORC2 in the development of myelinating cells and during remyelination after injury. To achieve these goals we will use conditional floxed alleles in the mouse that target two critical subunits of the mTOR complexes, raptor (mTORC1) and rictor (mTORC2). These mice are already available in the host laboratory. Using well established Cre recombinase expressing mouse strains, we will eliminate rictor and raptor individually and in combination specifically in developing Schwann cells in the PNS, as well as in mature Schwann cells followed by peripheral nerve injury. If time allows, we will perform complementary experiments in the CNS, using oligodendrocyte-specific gene knock out mice. The work will be embedded in ongoing work in the host laboratory examining the functional role of mTORC1 and mTORC2 in neural stem cell lineage decisions.'

Introduzione (Teaser)

Dissecting the basic principles of myelination has important ramifications for clinical neuroscience. With this in mind, a European study concentrated on the role of the mammalian target of rapamycin (mTOR) pathway in myelin production.

Descrizione progetto (Article)

Central to proper neuronal signal transmission is the myelination of axons. This acts as an insulator while maintaining signal strength during signal propagation. In disorders such as multiple sclerosis, the loss of the myelin sheath has devastating consequences in the normal function of the nervous system. Understanding the molecular processes responsible for myelination could provide future therapeutic solutions for demyelinating conditions.

In this context, scientists on the EU-funded 'The functions of mTOR complex subunits Rictor and Raptor in myelination' (MTORC IN MYELINATION) project were interested in the role of the mTOR pathway. mTOR signalling is a central regulator of cell growth and metabolism, and is intimately linked with PI3K-Akt signalling. The latter pathway seems to be involved in regulating myelin production through Schwann cells and subsequent coating of neurons.

MTORC IN MYELINATION members focused on the role of mTOR signalling in the peripheral nervous system. To this end, researchers deleted the subunits Raptor and Rictor in the two mTOR complexes mTORC1 and mTORC2, respectively. They then assessed the effects of deletion on myelin production in Schwann cells. They also analysed nerves from transgenic knockout mice at different time points of development to delineate the induced morphological and biochemical alterations.

The nerves lacking Raptor exhibited impaired myelination, both during development and in regeneration after injury. Signalling pathways downstream of mTOR were also severely affected, resulting in defective myelin production.

The data generated during the study underscore the importance of the mTOR pathway in functional myelin production and provide novel targets for therapeutic intervention. Pharmacological activation of mTOR which is being explored elsewhere could also find application for the treatment of demyelinating disorders.