: The myelin sheath that insulates peripheral nerve fibers is critical for efficient conduction of nerve signals through motor and sensory nerves. Myelin is produced by Schwann cells in a developmental process that is triggered by their association with developing axons. Several peripheral neuropathies-including Charcot-Marie-Tooth disease (CMT), Dejerine-Sottas Syndrome (DSS), and Congenital Hypomyelinating Neuropathy (CHN}-are caused by deficits in myelin formation and maintenance, and mutations in the gene coding for the EGR2 transactivator have recently been associated with these diseases. These results confirm previous work showing that the EGR2/Krox-20 is a critical regulator of myelin formation in mouse development. The goal of this application is to elucidate the mechanisms of transcriptional control that become altered in peripheral nerve diseases associated with EGR2 mutations. Several neuropathy-associated mutations inhibit DNA-binding by EGR2, but all of these mutations are dominant. This finding is surprising since only one functional allele of EGR2/Krox-20 is sufficient for myelin formation in mice. To understand the mechanism by which the dominant mutants cause peripheral neuropathies, microarray analysis will be used to identify genes that become deregulated by expression of dominant EGR2 mutants. The evidence suggests that the dominant mutants effectively sequester a critical cofactor of EGR2 activity, and studies of protein-protein interactions will be employed to identify this cofactor. Finally, one of the EGR2 mutations alters a domain that interacts with the NAB family of corepressor/coactivator proteins. This recessive mutation therefore strongly implicates the NAB proteins as important regulators of myelination, and microarray analysis will again be used to investigate how NAB proteins modify expression of the EGR2 gene network. Finally, expression of dominant negative NAB proteins will be used to investigate the functional role of NAB proteins in myelination of peripheral nerves.
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