Neuropathy-Associated Egr2 Mutants Disrupt ative Activation of Myelin Prot

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Neuropathy-Associated Egr2 Mutants Disrupt ative Activation of

Myelin Protein Zero by Egr2 and Sox10

http://mcb.asm.org/cgi/content/abstract/27/9/3521

E. LeBlanc,1 M. Ward,2 and Svaren1,2*

Molecular and Cellular Pharmacology Program, University of Wisconsin—

Madison, Madison, Wisconsin 53706,1 Department of Comparative

Biosciences, School of Veterinary Medicine, University of Wisconsin—

Madison, Madison, Wisconsin 537062

Dominant mutations in the early growth response 2 (Egr2/Krox20)

transactivator, a critical regulator of peripheral myelin

development, have been associated with peripheral myelinopathies.

These dominant mutants interfere with the expression of genes

required for myelination by Schwann cells, including that for the

most abundant peripheral myelin protein, Myelin protein zero (Mpz).

In this study, we show that Egr2 mutants specifically affect an Egr2-

responsive element within the Mpz first intron that also contains

binding sites for the transcription factor Sox10. Furthermore, Egr2

activation through this element is impaired by mutation of the Sox10

binding sites. Using chromatin immunoprecipitation assays, we found

that Egr2 and Sox10 bind to this element in myelinating sciatic

nerve and that a dominant Egr2 mutant does not perturb Egr2 binding

but rather attenuates binding of Sox10 to the Mpz intron element.

Sox10 binding at other sites of Egr2/Sox10 synergy, including a

novel site in the Myelin-associated glycoprotein (Mag) gene, is also

reduced by the dominant Egr2 mutant. These results provide the first

demonstration of binding of Egr2/Sox10 to adjacent sites in vivo and

also demonstrate that neuropathy-associated Egr2 mutants antagonize

binding of Sox10 at specific sites, thereby disrupting genetic

control of the myelination program.