Establishing Membrane Domains in Myelinated Nerve

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DESCRIPTION (provided by applicant): The rapid propagation of nerve impulses in myelinated nerve depends on its segregation into specialized membrane domains. Myelin segments along the nerve are interspersed by the unmyelinated nodes of Ranvier that contain clusters of sodium channels and serve to regenerate the action potential. On both sides of the node, septate-like junctions tightly attach the terminal myelin loops to the axon membrane. These paranodal junctions physically segregate the sodium channel clusters at the node from potassium channel clusters at the juxtaparanode just underneath the myelin. The molecular interactions that control the formation and maintenance of specialized membrane domains in myelin remain poorly understood. We have established an important function for Contactin in the formation of the septate-like paranodal junctions in both the CNS and PNS (Boyle et al., 2001; and in preparation). Contactin associates with Caspr (Contactin-associated Protein) and this interaction is necessary for Caspr trafficking to the axon membrane where the complex engages in junctional adhesion. However, little is known about how the expression of the Contactin-Caspr complex is regulated at central and peripheral paranodes. We have identified a novel Caspr-interacting protein that may regulate the availability and stability of the Caspr-Contactin complex on neuronal cell surfaces. Nothing is currently known about the distribution and function of this novel protein within cells and in the intact nervous system. The goal of this proposal is to reveal the functional association of this novel protein with Caspr and determine how this interaction regulates myelin assembly and function. This work will shed new light on the regulation of a protein complex that is vital for the development and function of myelin. Understanding the molecular signals that control the assembly, disassembly and compartmentalized localization of protein complexes in myelin will help in the design of strategies aimed at preventing and restoring proper functions in individuals affected by demyelinating diseases.