Myelination in the PNS is accompanied by a large induction of the myelin protein zero (Mpz) gene to produce the most abundant component in peripheral myelin. Analyses of knockout mice have shown that the EGR2/Krox20 and Sox10 transcription factors are required for Mpz expression. Our recent work has shown that the dominant EGR2 mutations associated with humanperipheral neuropathies cause disruption of EGR2/Sox10 synergy at specific sites, including a conserved enhancer element in the first intron of the Mpz gene. Further investigation of EGR2/Sox10 interactions reveals that activation of the Mpz intron element by EGR2 requires both Sox10-binding sites. In addition, both Egr1 and Egr3 cooperate with Sox10 to activate this element, which indicates that this capacity is conserved among Egr family members. Finally, a conserved composite structure of EGR2/Sox10-binding sites in the genes encoding Mpz, myelin-associated glycoprotein and myelin basic protein genes was used to screen for similar modules in other myelin genes, revealing a potential regulatory element in the periaxin gene. Overall, these results elucidate a working model for developmental regulation of Mpz expression, several facets of which extend to regulation of other peripheral myelin genes.
