MMP2-9 Cleavage of Dystroglycan Alters the Size and Molecular Composition of Schwann Cell Domains

Abstract

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.

Non-redundant function of dystroglycan and β1 integrins in radial sorting of axons

“…4A,C and Table 3). Finally, -dystroglycan glycosylation, which increases as nerves mature (Court et al, 2011), was significantly reduced in 1 integrin-null nerves. Collectively, these data suggest that dystroglycan acts after 1 integrin during axonal sorting.…”

A role for dystroglycan in the pathophysiology of acute leukemic cells

“…Changes in -Dg glycosylation may also play a role in cancer progression [16,17], which may have an important anti-tumorigenic function [14]; in addition, aberrant degradation of -Dg through MMP-2 and MMP-9 has been recorded as a relevant event observed in several tumor cell lines and in inflammatory diseases [16,18].…”

Matrix Metalloproteinase-14 Both Sheds Cell Surface Neuronal Glial Antigen 2 (NG2) Proteoglycan on Macrophages and Governs the Response to Peripheral Nerve Injury

“…laminin) from degradation, suppressing the algesic action of MMP-2 (21), and stimulating the regenerative program in the sensory neurons, the selective, local, and short term inhibition of MMP-14 activity promoted axonal growth and reversed the established hypersensitivity arising from PNS damage. Caution, however, is required in developing the sustained or late stage MMP-14 inhibitor therapy as this therapy may also target certain functions that are beneficial to nerve repair, such as the MMP-2-mediated degradation of inhibitory CSPGs (25,26) and myelination (20,64,65).…”