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J. Biol. Chem., Vol. 281, Issue 9, 5453-5460, March 3, 2006

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Direct Regulation of Myelin Protein Zero Expression by the Egr2 Transactivator^*

Scott E. LeBlanc¹, Sung-Wook Jang, Rebecca M. Ward^¶, Lawrence Wrabetz^||2, and John Svaren^¶3

From the Molecular and Cellular Pharmacology Program, the Graduate Program in Cellular and Molecular Biology, and the ^¶Department of Comparative Biosciences, School of Veterinary Medicine, University of Wisconsin, Madison, Wisconsin 53706 and the ^||San Raffaele Scientific Institute, Dipartimento di Ricerca Biologica e Technologica, 20132 Milan, Italy

During myelination of the peripheral nervous system, the myelin protein zero (Mpz) gene is induced to produce the most abundant protein component (P₀) of mature myelin. Although the basal embryonic expression of Mpz in Schwann cells has been attributed to regulation by Sox10, the molecular mechanism for the profound up-regulation of this gene during myelination has not been established. In this study, we have identified a highly conserved element within the first intron of the Mpz gene, which contains binding sites for the early growth response 2 (Egr2/Krox20) transcription factor, a critical regulator of peripheral nerve myelination. Egr2 can transactivate the intron element, and the induction is blocked by two known repressors of Egr2 activity. Using chromatin immunoprecipitation assays, we find that Egr2 binds in vivo to the intron element, but not to the Mpz promoter. Known inducers of Mpz expression such as forskolin and insulin-like growth factor-1 also activate the element in an Egr2-dependent manner. In addition, we found that Egr2 can act synergistically with Sox10 to activate this intron element, suggesting a model in which cooperative interactions between Egr2 and Sox10 mediate a large increase in Mpz expression to the high levels found in myelinating Schwann cells.

Received for publication, November 11, 2005 , and in revised form, December 21, 2005.

^* This work was supported in part by grants from the Muscular Dystrophy Association and National Institutes of Health Grant HD41590 (to J. S.) and a core grant from the Waisman Center from the NICHD National Institutes of Health Grant P30 HD03352. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Supported by National Institutes of Health Training Grant T32 GM08688.

² Supported by NINDS National Institutes of Health Grants NS043560, NS045630, and NS055256 and Telethon, Italy.

³ To whom correspondence should be addressed: 2015 Linden Dr., School of Veterinary Medicine, Madison, WI 53706. Tel.: 608-263-4246; Fax: 608-263-3926; E-mail: jpsvaren{at}wisc.edu.

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