GENETIC CONTROL OF SCHWANN CELL MYELINATION

描述(摘自申请者的摘要)：尽管医学上很重要 脱髓鞘疾病的衰弱作用证明了髓鞘的毒性， 对控制髓鞘的遗传调控机制知之甚少 综合。轴突接触通过未知的方式触发髓鞘形成 信号(S)，其中许多可以通过处理雪旺细胞来模仿 腺苷环化酶激活剂福斯可林。POU结构域转录因子Oct-6 (也称为Tst-1或SCIP)是Forskolin诱导的基因之一。 缺乏Oct-6的小鼠的表型表明，它在 控制外周髓鞘形成的时间和速度，但机制 它是通过什么方式做到这一点的还不得而知。屏幕上显示了其他受forsklin控制的内容 基因产生了ERK2特异性磷酸酶MKP-3的克隆，并且 鞘氨醇-1磷酸(S1P)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的首次 这项申请的具体目标是研究它们在 雪旺细胞及其激活分化标志物的能力，如 OCT-6在坐骨神经中的表达，其中五种的功能和/或识别是 未知。本应用程序第二个特定目标是描述这些 OCT-6进一步诱导基因表达。被激活的两个已知基因 OCT-6、细胞质LIM结构域蛋白CRP2与脂肪酸转运 髓鞘蛋白P2，提示细胞骨架重排或脂肪酸运输 作为髓鞘形成的限速步骤。这两个基因都含有可能的Oct-6 它们的启动子中的结合位点。OCT-6直接调控的假说 这些基因的表达将在第三个特定目标中进行测试 申请。在第四个具体目标中，提出了对出生后的研究 Oct-6在缺乏Oct-6基因的小鼠外周髓鞘形成中的作用 在雪旺细胞中。

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.