EXTRACELLULAR MATRIX AND SCHWANN CELL DIFFERENTIATION

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The ability of Schwann cells to differentiate and relate to neurons is an extremely important aspect of both normal development and repair of the peripheral nervous system (PNS). A key stage in glial differentiation involves the organization of extracellular matrix (ECM). Whereas numerous ECM molecules are present during the early stages of PNS morphogenesis, the mature basement membranes (basal and reticular laminae) are not organized until the later developmental stages when axons are ensheathed by Schwann cells. The molecular mechanisms involved in matrix formation must be established in order to understand the events controlling PNS development. ECM molecules which remain in the nerve after axotomy are also hypothesized to influence the regeneration of neurons; however, the molecules involved have not been thoroughly studied. Experiments are proposed to examine the disposition of extracellular matrix molecules in vivo in the adult, rat peripheral nerve and in peripheral nerve cells grown in culture. The studies utilize a tissue culture system in which Schwann cells are established in several stages of differentiation and a multidisciplinary approach using immunohistochemical and biochemical techniques is employed to analyse both the synthesis and organization of matrix molecules into intact tissue. In the first set of experiments, antibodies directed against matrix molecules are used to determine the cellular origin and final location of specific antigens associated with Schwann cells before, during and after neuronally induced glial differentiation. Experiment #2 is proposed to test the possibility that Schwann cells in the early stages of differentiation synthesize matrix molecules but do not organize these antigens into intact tissue. Experiment #3 is proposed to study the role of neuronal contact with respect to the synthesis of ECM molecules by Schwann cells. The final experiments (#4) examine the effect of matrix molecules on the morphology, mitotic index and synthetic capabilities of Schwann cells. Data resulting from this proposal addresses the hypothesis that the formation of ECM occurs in a sequential, multistep manner which in turn regulates and is regulated by the differentiation of Schwann cells.