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Concepts and project objectives

The characteristic appearance of white matter in the nervous system results from a remarkable cellular structure called myelin. This membraneous sheath is wrapped around axons by dedicated glial cells, thereby allowing the rapid propagation of impulses along the axons. The importance of myelin is underscored by the many neurological diseases that are caused by loss or destabilization of the myelin sheath, such as multiple sclerosis, leukodystrophies and peripheral neuropathies.

The formation and maintenance of myelin by Schwann cells and oligodendrocytes results from a continuous molecular dialogue with the neuronal axon. However, despite the vast importance of myelin for the normal physiological function of the nervous system, the molecular mechanisms underlying axon-glial communication in health and disease still remain largely unknown. Consequently, the therapeutic options for these disorders are very limited.

The current proposal aims to bridge this gap in our knowledge. Thus, the overall aim of this focused, collaborative effort is to push our understanding of myelination and myelination-related diseases beyond the state of the art and to identify new targets for pharmaceutical intervention to aid the regenerative capacity of the nervous system.

Currently, the leading paradigm directing our understanding of ensheathment, myelination and myelin-related disease is the interaction between axons and Schwann cells in the peripheral nervous system (PNS). All of the members of this consortium are major contributors to this paradigm. The PNS offers many experimental advantages: the possibility to model hereditary neuropathies in mice, to study myelination in well-defined co-culture systems and to manipulate the system through transgenesis and gene targeting techniques. To realize our aims, this consortium will concentrate its research on the peripheral nervous system. Discoveries made in peripheral axon-glial cell signalling will provide insight into central nervous system myelination and also its diseases, which are often too complex to reveal the underlying molecular mechanisms.

In our research plan we will take a comprehensive approach towards elucidating axon-glial interactions in myelination and myelin-related diseases of the nervous system.

Our specific aims are:

  1. To identify the molecular mechanisms that lead to initial engagement of axons by glial cells.
  2. To elucidate the glial cell-intrinsic mechanisms that control myelin formation.
  3. To identify the molecules and mechanisms underlying glial cell driven axonal specialization.

To unravel the pathogenic mechanism underlying demyelinating neuropathies and to develop cell-based assays to test potential therapeutic agents.