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Max-Planck-Gesellschaft
Max-Planck-Institut für Experimentelle Medizin
Prof. Klaus-Armin Nave

Myelin and experimental mouse genetics

Motor functions and higher cognitive processes depend on myelination of axons and long-term preservation of the white matter. Myelin originates from outgrowing glial processes that spirally ensheath axon segments, such that the compact membrane structure provides electrical insulation. This is the basis for rapid saltatory impulse conduction in the nervous system. Additionally, myelinating glial cells are required to maintain long-term axonal integrity.

Myelin is elaborated differently in the central and peripheral nervous system (by oligodendrocytes and Schwann cells, respectively). This provides the opportunity to compare how two cell types form myelin with overlapping but non-identical sets of genes. Structural proteins of myelin are involved at several stages of development: glial process outgrowth, axon recognition, and ensheathment at early time points, and later extensive intracellular and extracellular membrane interactions that underlie spiral wrapping and myelin compaction. In addition to this structural function, myelin proteins play a role in axon-glial signaling. Our research focuses on the molecular functions of myelin proteolipid protein (PLP), 2´,3´-cyclic nucleotide 3´-phosphodiesterase (CNP), peripheral myelin protein 22 (PMP22), and neuregulin1 to erbB-receptor signaling.

Brain diseases that have been associated with defects of CNS myelin range from severe myelin loss in leukodystrophies (Pelizaeus-Merzbacher disease, Adrenoleukodystrophy) and in multiple sclerosis, to very subtle myelin abnormalities in schizophrenia.

Remarkably little is known about the basic aspects of myelin assembly. What axon signals regulate myelin membrane growth? How does myelin grow spirally around the axon? Where is new membrane added into the growing sheath? What proteins, in addition to the few known ones, reach the myelin sheath? What is the molecular machinery to enrich lipids in myelin biogenesis? What is the molecular nature of long-term axonal support by myelinating glia? Is there a pharmacological treatment for rodent models of human CNS leukodystrophies or peripheral neuropathies?




Figure: Electron micrograph and schematic depiction of myelin and its major membrane proteins. Mutations in human hereditary white matter diseases have been identified in several myelin proteins (in red).



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