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

杜氏肌营养不良症（DMD）是一种X连锁隐性遗传的致死性神经肌肉疾病。1987年，DMD的基因缺陷被发现，其致病蛋白被命名为dystrophin。在过去的10年中，肌营养不良蛋白被阐明为与许多细胞膜糖蛋白（包括肌营养不良蛋白聚糖）复合以形成肌营养不良蛋白-糖蛋白复合物的细胞骨架蛋白。肌营养不良聚糖。由单个基因编码，并通过翻译后加工切割成两种蛋白质α-和β-肌营养不良聚糖。为了开始阐明肌营养不良蛋白聚糖的生理功能，我们对骨骼肌和周围神经中的肌营养不良蛋白聚糖进行了生化和细胞生物学表征。结果表明：（1）周围神经表达肌营养不良蛋白聚糖复合物，而不表达肌聚糖复合物。(2)X-肌营养不良蛋白聚糖是一种细胞外层粘连蛋白和聚集蛋白结合蛋白，其通过施旺细胞中的跨膜蛋白β-肌营养不良蛋白聚糖锚定在细胞膜上。(3)cz-肌营养不良聚糖的糖基化，特别是唾液酸化介导层粘连蛋白-1和2与α-肌营养不良聚糖的结合。(4)β-肌营养不良蛋白聚糖的胞质结构域锚定至Dpi 16（一种肌营养不良蛋白同种型），主要经由其在许旺细胞中的胞质结构域的15个C-末端氨基酸。我们还表征了肌营养不良蛋白聚糖在神经鞘瘤细胞与层粘连蛋白粘附中的作用，并发现肌营养不良蛋白聚糖在与Lam mm的粘附中起着重要作用。总之，我们的结果支持肌营养不良蛋白聚糖作为主要细胞粘附分子在不仅骨骼肌而且雪旺细胞的细胞膜中的作用。由于缺乏层粘连蛋白-2导致周围神经髓鞘形成障碍的患者与一个子集的先天性肌营养不良症和dy小鼠，我们建议层粘连蛋白-2与肌营养不良蛋白聚糖的相互作用中发挥了重要作用的雪旺细胞髓鞘形成。

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.