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

Duchenne肌营养不良症(DMD)是一种X连锁的隐性致死性神经肌肉疾病。导致DMD的基因缺陷于1987年被发现，并将其致病蛋白命名为dystrophin。在过去的10年中，dystrophin被澄清为一种细胞骨架蛋白，它与包括dystrophin在内的许多细胞膜糖蛋白复合，形成dystrophin-糖蛋白复合体。营养不良葡聚糖。由单个基因编码，通过翻译后加工裂解成两种蛋白质--α-和β-肌营养不良聚糖。为了开始阐明营养不良聚糖的生理功能，我们对骨骼肌和周围神经中的营养不良聚糖进行了生化和细胞生物学特性的研究。结果表明：(1)肌营养不良蛋白聚糖复合体在周围神经中有表达，而肌聚糖复合体不表达。(2)在雪旺细胞中，X-肌营养不良蛋白是一种细胞外层粘连蛋白和集聚蛋白结合蛋白，由一种跨膜蛋白β-肌营养不良蛋白锚定在细胞膜上。(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)在雪旺细胞中，β-dystroglan的胞浆结构域主要通过其胞质结构域的15个C-末端氨基酸与dystrophin亚型DPI-16连接。我们还研究了肌营养不良多聚糖在神经鞘瘤细胞与层粘连蛋白黏附中的作用，发现肌营养不良多聚糖在黏附LAM-MM中起重要作用。综上所述，我们的结果支持肌营养不良蛋白聚糖作为主要的细胞黏附分子在骨骼肌和雪旺细胞细胞膜中的作用。由于层粘连蛋白-2的缺乏导致了先天性肌营养不良症患者和Dy鼠的周围神经髓鞘损伤，我们认为层粘连蛋白-2与营养不良多糖的相互作用在雪旺细胞髓鞘形成中起着重要作用。

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.