During the development of the central nervous system, specialized glia, oligodendrocytes, extend and wrap their plasma membrane around axons to form tightly packed membrane stacks that provide electrical insulation. Axonal insulation by myelin facilitates rapid nerve conduction and is essential for neuronal metabolism. Damage to the myelin sheath as it for example occurs in multiple sclerosis results in severe neurological disability not only by slowing down nerve conduction, but also as a result of neurodegeneration. Our main goal is to develop strategies to promote remyelination in demyelinating diseases. To realize this goal we need to understand how myelin is formed during normal development. The focus of this project will therefore be on the molecular mechanism of myelination and in particular on the role of neuron-glia communication in this process. We plan to study the mechanisms of myelin membrane growth and test a novel model of membrane extension. We hypothesize that the myelin membrane grows by the lateral diffusion of plasma membrane driven by a tension gradient that is formed by membrane trafficking events. We propose that neurons control this process by regulating the balance of exo- and endocytosis in oligodendrocytes. Furthermore, we would like to test a novel model of myelin membrane assembly, in which we suggest that myelin is formed after a gradual maturation of the plasma membrane that is regulated by neurons and require MBP. We will also investigate the signalling from oligodendrocytes to neurons by analyzing the function of small membrane vesicles, exosomes that we have recently found to be released by oligodendrocytes. Our goal is to understand how these signalling systems act on the cellular machinery that generates myelin. We hope that this approach will not only provide key insights into the development of myelin, but also help us to find new druggable targets for demyelinating diseases.
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