LeBlanc Scott E, Jang Sung-Wook, Ward Rebecca M, Wrabetz Lawrence, Svaren John
Molecular and Cellular Pharmacology Program, School of Veterinary Medicine, University of Wisconsin, 2015 Linden Drive, Madison, WI 53705, USA.
J Biol Chem. 2006 Mar 3;281(9):5453-60. doi: 10.1074/jbc.M512159200. Epub 2005 Dec 22.
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.
在周围神经系统的髓鞘形成过程中，髓鞘蛋白零（Mpz）基因被诱导产生成熟髓鞘中最丰富的蛋白质成分（P(0)）。尽管雪旺细胞中Mpz的基础胚胎表达归因于Sox10的调控，但该基因在髓鞘形成过程中深度上调的分子机制尚未明确。在本研究中，我们在Mpz基因的第一个内含子中鉴定出一个高度保守的元件，其含有早期生长反应2（Egr2/Krox20）转录因子的结合位点，Egr2是周围神经髓鞘形成的关键调节因子。Egr2可反式激活该内含子元件，且这种诱导作用被两种已知的Egr2活性抑制剂所阻断。通过染色质免疫沉淀分析，我们发现Egr2在体内与该内含子元件结合，但不与Mpz启动子结合。已知的Mpz表达诱导剂，如福斯可林和胰岛素样生长因子-1，也以Egr2依赖的方式激活该元件。此外，我们发现Egr2可与Sox10协同作用来激活该内含子元件，这提示了一种模型，即Egr2与Sox10之间的协同相互作用介导了Mpz表达大幅增加至在髓鞘形成雪旺细胞中所发现的高水平。
