Axonal insulation is of fundamental importance for the proper propagation of action potentials. Our laboratory is investigating the genetic and molecular basis of complex, and reciprocal interactions between various types of glial cells, which play a key role in axonal insulation and blood-brain barrier (BBB) formation during Drosophila development. We have demonstrated that septate junctions between perineurial and inner glial cells play an essential role in axonal insulation and BBB formation. We identified the first molecular component of the glial-glial septate junctions, which was named Neurexin IV.

Mutations in Neurexin IV result in loss of septate junctions between glial cells and breakdown of the BBB, and eventual paralysis. Mutant embryos do not show any muscle contraction propagation waves that are critical for hatching and survival. Currently, genetic screens with enhancer detection using GFP expression are underway to identify additional molecular components at the septate junctions, and to understand the mechanisms of BBB formation and axonal insulation. We have extended our studies into vertebrates, where axonal insulation is achieved by myelination carried out by glial cells (Schwann cells and oligodendrocytes). The myelinated nerve fibers are organized into distinct domains that are necessary for rapid saltatory conduction. These domains include the nodes of Ranvier and the flanking paranodal regions where myelin loops closely appose and form specialized septate-like junctions with the axonal axolemma. We recently showed that these junctions contain a Drosophila Neurexin IV related protein, Caspr/Paranodin (NCP1). The NCP1 mutant mice at 2-3 weeks of age exhibit tremors, ataxia, and paralysis. In the absence of NCP1, paranodal junctions fail to form, and the organization of the paranodal loops is disrupted. Another highly conserved septate junction protein, Contactin, which interacts with NCP1 is undetectable in the mutant paranodes, and potassium channels are displaced from the juxtaparanodal into the paranodal domains. These defects result in a severe decrease in peripheral nerve conduction velocity, and thus cause paralysis, demonstrating a critical role for NCP1 in the delineation of specific axonal domains and the axon-glia interactions.

Current studies are focused on investigating the genetic and molecular basis of the glial-glial septate junctions in Drosophila, and elucidation of the mechanisms by which vertebrate axons become organized into specialized domains. We are also interested in identifying the molecular complexes that are involved at the interface of axons and glial cells in both the systems, and how loss of these molecules affects conduction of nerve impulses and synaptogenesis