CHARACTERIZATION OF DYSTROGLYCAN-LAMININ INTERACTION IN PERIPHERAL MYELINOGENESIS AND ITS DISTURBANCE

杜氏肌营养不良症（DMD）是一种x连锁隐性致死性神经肌肉疾病。1987年发现了导致DMD的基因缺陷，并将致病蛋白命名为肌营养不良蛋白。在过去的10年里，肌营养不良蛋白被澄清为一种细胞骨架蛋白，与许多细胞膜糖蛋白（包括肌营养不良聚糖）络合，形成肌营养不良蛋白-糖蛋白复合物。Dystroglycan。由一个基因编码，并通过翻译后加工分裂成两种蛋白-和-三磷酸糖酐。为了开始阐明糖质异常的生理功能，我们对骨骼肌和周围神经中的糖质异常进行了生化和细胞生物学表征。我们得到的结果表明：(1)外周神经中表达肌糖聚糖复合物，而不是肌糖聚糖复合物。(2)在雪旺氏细胞中，x-三聚糖酐是一种胞外层粘连蛋白和agrin结合蛋白，通过跨膜蛋白β -三聚糖酐锚定在细胞膜上。(3)糖基化，特别是唾液酰化，介导层粘连蛋白-1和2与α -三聚糖醛酸的结合。(4)在雪旺细胞中，β -肌营养不良聚糖的胞质结构域主要通过其胞质结构域的15个c端氨基酸锚定在Dpi - 16和肌营养不良蛋白异构体上。我们还描述了糖异常蛋白在神经鞘瘤细胞与层粘连蛋白粘附中的作用，并发现糖异常蛋白在神经鞘瘤细胞与层粘连蛋白的粘附中起重要作用。总之，我们的研究结果支持糖异常蛋白作为骨骼肌和雪旺细胞细胞膜上的主要细胞粘附分子的作用。由于层粘连蛋白-2的缺乏导致先天性肌营养不良患者和dy小鼠周围神经髓鞘异常，我们提出层粘连蛋白-2与糖异常蛋白的相互作用在雪旺细胞髓鞘形成中起重要作用。

Duchenne muscular dystrophy (DMD) is an X-linked recessive, lethal neuromuscular disease. The gene defect causing DMD was identified in 1987 and the causative protein was named dystrophin. Over the last 10 years, dystrophin was clarified to be a cytoskeletal protein complexed with a number of cell membrane glycoproteins, including dystroglycan, to form the dystrophin-glycoprotein complex. Dystroglycan. is encoded by a single gene and cleaved into two proteins alpha- and beta-dystroglycan by posttranslational processing. To begin to elucidate the physiological functions of dystroglycan, we performed biochemical and cell biological characterization of dystroglycan in skeletal muscle and peripheral nerve. We obtained results that inidicate the following : (1) The dystroglycan complex, but not the sarcoglycan complex, is expressed in peripheral nerve. (2) x-dystroglycan is an extracellular laminin- and agrin-binding protein anchored to the cell membrane by a transmembrane protein beta-dystroglycan in Schwann cells. (3) Glycosylation, sialylation in particular, of cz-dystroglycan mediates the binding of laminin-1 and 2 to alpha-dystroglycan. (4) The cytoplasmic domain of beta-dystroglycan is anchored to Dpi 16, an dystrophin isoform, mainly via the 15 C-terminal amino acids of its cytoplasmic domain in Schwann cells. We also characterized the role of dystroglycan in the adhesion of schwannoma cells to laminin and found that dystroglycan plays an important role in the adhesion to lam mm. All together, our results support a role for dystroglycan as a major cell adhesion molecule in the cell membrane of not only skeletal muscle but also Schwann cells. Since the deficiency of laminin-2 causes peripheral nerve dysmyelination in the patient with a subset of congenital muscular dystrophy and dy mice, we propose that the interaction of laminin-2 with dystroglycan plays an important role in the Schwann cell myelinogenesis.