| Our laboratory is investigating the complex, reciprocal interactions between axons and myelinating glia, i.e. Schwann cells in the peripheral nervous system and oligodendrocytes in the central nervous system. Axons promote the proliferation, survival and differentiation of these glial cells including, most dramatically, their formation of the myelin sheath. Glial cells, in turn, provide trophic factors that promote neuronal survival; they also regulate the organization of myelinated axons into distinct physiologic domains that promote the rapid and efficient propagation of action potentials via saltatory conduction. Elucidation of the juxtacrine signaling between these cells will be critical for an understanding of how myelinated nerves form and may provide important insights into the pathogenesis of demyelinating disorders. Our current studies are focused on three major areas. First, we are characterizing the role of the neuregulin-1 family of neuronal growth factors, and the downstream signaling pathways they activate, in glial cell genesis, differentiation and response to injury. Second, we are developing strategies to identify neuronal signals that promote myelination - signals that have been elusive to date. Lastly, we are investigating the mechanisms by which axons become organized into distinct longitudinal domain. These domains include the node of Ranvier, which contains high concentrations of sodium channels, the paranodal region, which contains specialized junctions that form between the axon and the terminal loops of the myelin sheath, and the juxtaparanodal region which is enriched in delayed rectifier potassium channels. Recent studies suggest these junctions are comprised of a multiprotein complex of cell adhesion molecules and that they function to delineate the distribution of sodium and potassium channels. We are characterizing other components of these junctions and the interactions responsible for node formation using myelinating cocultures, biochemical methods and genetic engineered murine lines. |
