CONTROL OF SCHWANN CELL DIFFERENTIATION

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DESCRIPTION (from the applicant's abstract): The objective of this proposal is to understand how Schwann cells integrate diverse environmental signals during development of, and recovery from, disease or trauma to peripheral nerve. The long-term goals are to determine how Schwann cells respond to signals from extracellular matrix (ECM), axons, and neighboring Schwann cells in order to coordinate growth and differentiation into myelin-forming cells. Toward this goal, the Dr. Fernandez-Valle and her colleagues have studied ECM dependent signaling activated by Schwann cell adhesion to laminin, an ECM protein in the Schwann cell basal lamina. During the last grant period, focal adhesion kinase, paxillin, fyn kinase, and merlin (a tumor suppressor encoded by the neurofibromatosis type-2 gene product) were found to be involved in beta-1 integrin-dependent signaling during Schwann cell myelination in vitro. The mechanism by which merlin suppresses tumor formation the nervous system is unknown. The results implicate merlin in a beta-1 integrin dependent signaling pathway during Schwann cell differentiation. The hypothesis will be tested that merlin mediates a "dialogue" between signaling pathways; one activated by glial growth factor binding to HER2/HER3 receptors and another activated by laminin binding to beta-1 integrins on the Schwann cell surface. In this application, it is proposed to: 1) map beta-1 integrin upstream events by examining rho GTPases and their regulators; 2) map beta-1 integrin downstream events by examining mitogen-activated protein kinase and beta-1 integrin endocytosis; 3) look for "cross-talk" between pathways by conducting HER2/HER3 receptor and paxillin, merlin, and FAK reciprocal co-immunoprecipitations; and 4) carry out functional analyses using dominant negative and antisense oligonucleotide strategies. Isolated Schwann cell cultures and the in vitro myelination model consisting of Schwann cells co-cultured with neurons will be used. These are useful paradigms, allowing for functional analyses of proteins and application of all major biochemical, molecular, and cytological approaches. This information may relate to development of therapies for a) injuries to peripheral nerve, b) efforts to use Schwann cells as promoters of regeneration and remyelination in the central nervous system following trauma or disease, and 3) treatment or prevention of glial or other nervous system tumors occurring sporadically in the population or resulting from mutations in the neurofibromatosis type-2 gene.