Slutsky Shalom G, Kamaraju Anil K, Levy Alon M, Chebath Judith, Revel Michel
Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100, Israel.
J Biol Chem. 2003 Mar 14;278(11):8960-8. doi: 10.1074/jbc.m210569200.
Induction of myelin genes occurs around birth in the last stage of Schwann cells differentiation and is reactivated in case of nerve injury. Previous studies showed that activation of the gp130 receptor system, using as ligand interleukin-6 fused to its soluble receptor (IL6RIL6), causes induction of myelin genes such as myelin basic protein (MBP) and myelin protein zero (Po) in embryonic dorsal root ganglia Schwann cells. We also reported that in murine melanoma B16/F10.9 cells, IL6RIL6 causes a shut-off of melanogenesis mediated by a down-regulation of the paired-homeodomain factor Pax3. The present work demonstrates that these IL6RIL6-treated F10.9 cells undergo transdifferentiation to a myelinating glial phenotype characterized by induction of the transcriptional activities of both Po and MBP promoters and accumulation of myelin gene products. For both Po and MBP promoters, a repression by Pax3 and stimulation by Sox10 can be demonstrated. Because after IL6RIL6-treatment, Pax3 disappears from the F10.9 cells (as it does in mature myelinating Schwann cells) whereas the level of Sox10 rather increases, we modulated the relative level of these factors and show their involvement in the induction of myelin gene expression by IL6RIL6. In addition, however, we show that a C/G-rich CACC box in the Po promoter is required for activation by IL6RIL6, as well as by ectopic Sox10, and identify a Kruppel-type zinc finger factor acting through this CACC box, which stimulates Po promoter activity.
髓鞘基因的诱导发生在出生前后施万细胞分化的最后阶段，并且在神经损伤时会重新激活。先前的研究表明，使用与其可溶性受体融合的白细胞介素-6（IL6RIL6）作为配体激活gp130受体系统，可导致胚胎背根神经节施万细胞中髓鞘基因如髓鞘碱性蛋白（MBP）和髓鞘蛋白零（Po）的诱导。我们还报道，在小鼠黑色素瘤B16/F10.9细胞中，IL6RIL6通过下调配对同源结构域因子Pax3介导黑色素生成的关闭。目前的工作表明，这些经IL6RIL6处理的F10.9细胞会转分化为具有髓鞘形成能力的神经胶质细胞表型，其特征是Po和MBP启动子的转录活性诱导以及髓鞘基因产物的积累。对于Po和MBP启动子，可以证明Pax3的抑制作用和Sox10的刺激作用。因为在经IL6RIL6处理后，Pax3从F10.9细胞中消失（就像在成熟的髓鞘形成施万细胞中一样），而Sox10的水平反而增加，所以我们调节了这些因子的相对水平，并显示它们参与了IL6RIL6诱导的髓鞘基因表达。此外，我们还表明，Po启动子中富含C/G的CACC框是IL6RIL6以及异位Sox10激活所必需的，并鉴定了一种通过该CACC框起作用的Kruppel型锌指因子，它刺激Po启动子活性。
