Target expression of foreign genes in transgenic animals offers great potential for studying the interactions between axons and glial cells in the developing nervous system. Transgenic mice expressing the oncogene form SV40 virus (T-antigen) in Schwann cells of peripheral never develop a disorder of myelination that results in generalized paralysis. The proposed study will investigate the pathogenesis of T-antigen effects on Schwann cells, and will test the feasibility of specific targeting of transgene expression to the myelinating population of Schwann cells via regulatory sequences from the myelin-specific P0 gene. Whether T-antigen induces Schwann cell proliferation or Schwann cell death will be determined by in vivo labeling with tritiated thymidine followed by combined autoradiography and immunocytochemistry. The sources of proliferating cells in the peripheral neuropathy will be established. The demyelinating or hypomyelinating nature of the neuropathy will be determined in vivo through immunocytochemical and ultrastructural studies of unmyelinated grafts of the cervical sympathetic trunk transplanted into myelinated nerves. Specific targeting of transgene expression to myelinating Schwann cells will be accomplished by combining 5' flanking DBA sequences from the P0 gene with various structural genes. Cis-acting regulatory sequences in the P0 gene will be identified through the ability to direct tissue-specific and developmentally regulated expression of a growth hormone reporter gene. The domains of T- antigen that are responsible for the myelination disorder will be studied through the introduction of P0-T-antigen and P0-T-antigen mutants. The role that myelinating Schwann cells play in the development of peripheral nerve will be studied by cell-specific ablation, inducing suicide expressing of diphtheria toxin A chain with a P0-diphtheria toxin, fusion gene.
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