Direct regulation of myelin protein zero expression by the Egr2 transactivator.
During myelination of the peripheral nervous system, the myelin protein zero (Mpz) gene is induced to produce the most abundant protein component (P(0)) 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.
LeBlanc
Scott E
SE
Molecular and Cellular Pharmacology Program, School of Veterinary Medicine, University of Wisconsin, 2015 Linden Drive, Madison, WI 53705, USA.
Jang
Sung-Wook
SW
Ward
Rebecca M
RM
Wrabetz
Lawrence
L
Svaren
John
J
D000818:Animals; D002460:Cell Line; D055541:DEAD Box Protein 20; D053487:DEAD-box RNA Helicases; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D051767:Early Growth Response Protein 2 / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D006609:High Mobility Group Proteins / Q000235:genetics / Q000378:metabolism; D007438:Introns; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018993:Myelin P0 Protein / Q000235:genetics / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D020365:RNA Helicases / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D055757:SOXE Transcription Factors; D012583:Schwann Cells / Q000166:cytology / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
D004268:DNA-Binding Proteins; D051767:Early Growth Response Protein 2; C497327:Egr2 protein, mouse; D006609:High Mobility Group Proteins; D018993:Myelin P0 Protein; C490999:Nab2 protein, rat; D009363:Neoplasm Proteins; D012097:Repressor Proteins; D055757:SOXE Transcription Factors; C527924:Sox10 protein, mouse; C527925:Sox10 protein, rat; D014157:Transcription Factors; D055541:DEAD Box Protein 20; C485624:Ddx20 protein, mouse; D053487:DEAD-box RNA Helicases; D020365:RNA Helicases