GENETIC CONTROL OF SCHWANN CELL MYELINATION

描述（来自申请人的摘要）：尽管具有医学重要性， 脱髓鞘疾病的衰弱效应证明， 对控制髓鞘的遗传调节机制知之甚少 合成.轴突接触触发髓鞘形成通过迄今未知 信号，其中许多信号可以通过用 腺苷酸环化酶激活剂毛喉素。POU结构域转录因子Oct-6 (also称为Tst-1或SCIP）是由毛喉素诱导的基因之一。 缺乏Oct-6的小鼠的表型表明，它在以下方面起着关键作用： 控制周围髓鞘形成的时间和速度，但机制 而这一切，都是未知的。筛选额外的毛喉素调节 基因产生ERK 2特异性磷酸酶MKP-3的克隆， 1-磷酸鞘氨醇（S1 P）受体edg-3。为了更好地理解 这些信号转导分子在雪旺细胞分化中， 本申请的具体目的将研究它们在 雪旺细胞，以及它们激活分化标志物的能力， Oct-6在坐骨神经中的作用，其中5种的功能和/或特性分别为： 未知本申请的第二个具体目的是表征这些化合物。 Oct-6进一步诱导基因表达。两个已知的基因被激活， Oct-6、细胞质LIM结构域蛋白CRP 2和脂肪酸转运 髓鞘P2蛋白，提示细胞骨架重排或脂肪酸转运 作为髓鞘形成的限速步骤。这两个基因都具有推定的Oct-6 启动子中的结合位点。假设Oct-6直接调节 这些基因的表达将在本研究的第三个具体目标中进行测试。 应用程序.在第四个具体目标中，建议研究产后 Oct-6在外周髓鞘形成中的功能，使用仅缺乏该基因的小鼠 在雪旺氏细胞中。

DESCRIPTION (From the Applicant's Abstract): In spite of the medical importance of myelin, as evidenced by the debilitating effects of demyelinating diseases, little is known about the genetic regulatory mechanisms that control myelin synthesis. Axonal contact triggers myelination through as yet unknown signal(s), many of which can be mimicked in Schwann cells by treatment with the adenylyl cyclase activator forskolin. The POU domain transcription factor Oct-6 (also known as Tst-1 or SCIP) is one of the genes that is induced by forskolin. The phenotypes of mice that lack Oct-6 reveal that it plays a critical role in controlling the timing and rate of peripheral myelination, but the mechanisms by which it does so are unknown. A screen for additional forskolin-regulated genes produced clones for the ERK2-specific phosphatases MKP-3, and the sphingosine-1 phosphate (S1P) receptor edg-3. To better understand the role of these signal transduction molecules in Schwann cell differentiation, the first Specific Aim of this application will study their expression patterns in Schwann cells, and their ability to activate differentiation markers such as Oct-6 in sciatic nerve, of which the functions and/or identifies of five are unknown. The second Specific Aim of this application is to characterize these Oct-6 induced genes genes further. The two known genes that are activated by Oct-6, the cytoplasmic LIM domain protein CRP2, and the fatty acid transport protein myelin P2, suggest cytoskeletal rearrangement or fatty acid transport as rate-limiting steps in myelination. Both genes possess putative Oct-6 binding sites in their promoters. The hypothesis that Oct-6 directly regulates the expression of these genes will be tested in the third Specific Aim of this application. In the fourth Specific Aim, it is proposed to study postnatal functions of Oct-6 in peripheral myelination using mice that lack the gene only in Schwann cells.