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.

␣-Dystroglycan (␣-DG) was identified as a common receptor for lymphocytic choriomeningitis virus (LCMV) and several other arenaviruses including the human pathogenic Lassa fever virus. Initial work postulated that interactions between arenavirus glycoproteins and ␣-DG are based on protein-protein interactions. We found, however, that susceptibility toward LCMV infection differed in various cell lines despite them expressing comparable levels of DG, suggesting that posttranslational modifications of ␣-DG would be involved in viral receptor function. Here, we demonstrate that glycosylation of ␣-DG, and in particular, O mannosylation, which is a rare type of O-linked glycosylation in mammals, is essential for LCMV receptor function. Cells that are defective in components of the O-mannosylation pathway showed strikingly reduced LCMV infectibility. As defective O mannosylation is associated with severe clinical symptoms in mammals such as congenital muscular dystrophies, it is likely that LCMV and potentially other arenaviruses may have selected this conserved and crucial posttranslational modification as the primary target structure for cell entry and infection.

Dystroglycan (DG) is an adhesion molecule formed by two subunits, α (extracellular) and β (transmembrane) DG, which are codified by a single gene and form a continuous link from the extracellular matrix to the intracellular cytoskeleton. Reduction or loss of expression of DG has been observed in human cancer cell lines and primary tumors and has been suggested to promote tumor development and invasiveness.In this study, the human breast epithelial non-tumorigenic MCF10F and the breast cancer MCF7 cell lines were engineered to stably express an exogenous DG cDNA and the effects on the phenotype of both cell lines were evaluated. The MCF10F transfected cells displayed an increased expression of both DG subunits which was associated with inhibition of the anchorage-dependent growth, accumulation of cells in the G 0 /G 1 phase of the cell cycle and increased adhesion to a substratum. The MCF7 transfected cells were unable to restore α-DG despite an increased expression of the β-DG subunit. Anchoragedependent and independent growth and the in vivo tumorigenicity were reduced in these derivatives that also displayed a reduced adhesion to a substratum and were shown to release α-DG in the culture medium.These findings confirm and extend previous evidence that transformation of mammary epithelial cells is associated with loss of their ability to retain α-DG on the cell membrane. Moreover, they indicate that DG is involved in cell functions other than cell adhesion to the extracellular matrix, and that its loss of function might predispose to tumor progression by compromising regulatory controls over cell growth and proliferation.

Dystroglycan (DG) is an integral membrane receptor of extracellular matrix proteins, composed of two subunits alpha and beta derived from a common precursor. In brain DG is expressed in neurons, glia limitans, astrocytic endfeet around vessels and endothelial cells. We investigate whether DG may play a role in brain tumors. Western blot and immunofluorescence analysis showed that, while beta-DG subunit was present, the highly glycosylated alpha-DG subunit was strongly reduced in surgically derived human glioblastoma biopsies, in low passage patient-derived cultures and in glioma cell lines, U87MG and A172MG, but not in all glioma cell lines tested. Immunohistochemistry of tumor frozen sections revealed that the loss of a-DG was confined in the tumor area but not around blood vessels. Overexpression of DG decreased the growth rate of the glioma cell lines lacking the highly glycosylated alpha-DG subunit and the colony-forming efficiency. Clonogenic assay in presence of temozolomide showed an additive effect between DG overexpression and drug treatment. Our data suggest that DG may be involved in the progression of primary brain tumors