MMP2-9 cleavage of dystroglycan alters the size and molecular composition of Schwann cell domains.
MMP2-9 cleavage of dystroglycan alters the size and molecular composition of Schwann cell domains.
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DOI：
10.1523/jneurosci.0141-11.2011
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发表时间：
2011-08-24
期刊：
影响因子：
--
通讯作者：
Feltri ML
中科院分区：
文献类型：
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作者：
Court FA;Zambroni D;Pavoni E;Colombelli C;Baragli C;Figlia G;Sorokin L;Ching W;Salzer JL;Wrabetz L;Feltri ML
髓鞘神经胶质细胞表现出惊人的细胞结构，因为它们在多个轴和域上极化。这是如何发生的很大程度上尚不清楚。肌营养不良聚糖-肌营养不良蛋白复合物是髓鞘形成雪旺细胞功能所必需的。与其他组织类似，雪旺细胞中的肌营养不良聚糖复合物与不同肌营养不良蛋白家族成员一起定位在特定区域，从而促进极化。我们在此表明，基质金属蛋白酶 2 和 9 对肌营养不良聚糖的裂解（在大多数组织中被认为是病理性的）在正常神经中受到精细且动态的调节，并调节肌营养不良聚糖复合物的组成和雪旺细胞区室的大小。相比之下，在层粘连蛋白 211 缺乏模型 Dy2j/2j 小鼠的神经中，金属蛋白酶 2 和 9 增加，导致肌营养不良聚糖过度裂解和区室异常。裂解的药理学抑制可挽救 Dy2j/2j Schwann 细胞的细胞质缺陷。因此，受调节的裂解可能是在生理条件下调节蛋白质复合物组成的一般机制，而不受调节的加工是致病性的，并且是疾病治疗的靶点。
Myelinating glial cells exhibit a spectacular cytoarchitecture, because they polarize on multiple axes and domains. How this occurs is largely unknown. The dystroglycan-dystrophin complex is required for the function of myelin-forming Schwann cells. Similar to other tissues, the dystroglycan complex in Schwann cells localizes with different dystrophin-family members in specific domains, thus promoting polarization. We show here that cleavage of dystroglycan by matrix-metalloproteinases 2 and 9, an event that is considered pathological in most tissues, is finely and dynamically regulated in normal nerves and modulates dystroglycan complex composition and the size of Schwann cell compartments. In contrast, in nerves of Dy2j/2j mice, a model of laminin 211 deficiency, metalloproteinases 2 and 9 are increased causing excessive dystroglycan cleavage and abnormal compartments. Pharmacological inhibition of cleavage rescues the cytoplasmic defects of Dy2j/2j Schwann cells. Thus, regulated cleavage may be a general mechanism to regulate protein complex composition in physiological conditions, while unregulated processing is pathogenic and a target for treatment in disease.