Regulation of the PMP22 Gene through an Intronic Enhancer

April 1, 2011

The Journal of Neuroscience, 16 March 2011, 31(11): 4242-4250; doi: 10.1523

A. 1, Camila -Anido3, Rajini Srinivasan3, Krueger3,

Li-Wei Chang4, Rakesh Nagarajan4, and Svaren2,3

+ Author Affiliations

1Program in Cellular and Molecular Biology,

2Department of Comparative Biosciences, and

3Waisman Center, University of Wisconsin, Madison, Wisconsin 53705, and

4Department of Pathology and Immunology, Washington University School of

Medicine, Saint Louis, Missouri 63110

Abstract

Successful myelination of the peripheral nervous system depends upon induction

of major protein components of myelin, such as peripheral myelin protein 22

(PMP22). Myelin stability is also sensitive to levels of PMP22, as a 1.4 Mb

duplication on human chromosome 17, resulting in three copies of PMP22, is the

most common cause of the peripheral neuropathy Charcot-Marie-Tooth disease.

The transcription factor Egr2/Krox20 is required for induction of high level

expression of Pmp22 in Schwann cells but its activation elements have not yet

been determined.

Using chromatin immunoprecipitation analysis of the rat Pmp22 locus, we found a

major peak of Egr2 binding within the large intron of the Pmp22 gene. Analysis

of a 250 bp region within the largest intron showed that it is strongly

activated by Egr2 expression in reporter assays.

Moreover, this region contains conserved binding sites not only for Egr2 but

also for Sox10, which is also required for Schwann cell development.

Our analysis shows that Sox10 is required for optimal activity of the intronic

site as well as PMP22 expression. Finally, mouse transgenic analysis revealed

tissue-specific expression of this intronic sequence in peripheral nerve.

Overall, these data show that Egr2 and Sox10 activity are directly involved in

mediating the developmental induction of Pmp22 expression.

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